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Comparison of intramuscular absorption above and below the level of a spinal cord injury Spurrell, Valerie Jean 1992

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COMPARISON OF INTRAMUSCULAR ABSORPTIONABOVE ANDBELOW THE LEVEL OF A SPINAL CORD INJURYbyVALERIE JEAN SPURRELLB.S.N., The University of British Columbia, 1980A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFMASTER OF SCIENCE IN NURSINGinTHE FACULTY OF GRADUATE STUDIESSchool of NursingWe accept this thesis as conformingTHE UNIVERSITY OF BRITISH COLUMBIAMarch 1992© Valerie Jean Spurrell, 1992In presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.(Signature) Department of ^1 V v,R )^cThe University of British ColumbiaVancouver, CanadaDate^(.)/y\ 0-0/1 DE-6 (2/88)iiAbstractThis study was designed to determine the difference in drugabsorption between intramuscular injections given above and belowthe lesion in persons with a spinal cord injury.The theoretical framework identified three categories offactors known to influence serum drug absorption followingintramuscular injections: drug action, diffusion area, and bloodflow, with a focus on muscle innervation as one factor in theblood flow category.Hypotheses tested in this study were that serum trough andserum peak levels are greater and absorption time is shorter whenI.M. injections of gentamicin are given above the level of aspinal cord injury than when given below.The study used an experimental, repeated measures design withcounterbalancing and subjects acted as their own controls byreceiving injections both above and below the level of injury. Atotal of five serum samples were drawn before and after a seriesof injections in each site to determine any differences in serumdrug absorption.When it was not possible to obtain the sample size intended,case analysis was used to study the three subjects who enrolledin the study. Factors which may have influenced the difficultyin obtaining a larger sample are identified and discussed.The results of the study indicated that of the three cases,only in the first case were the serum trough and peak levelshigher following deltoid injections than following glutealinjections. The contrary results for the second and third casemay have been related to differences in the number of injectionsiiiand differences in the dosing intervals.The time between serum samples was too great to accuratelydifferentiate the absorption times, but pharmacokinetic valuesassociated with the elimination phase suggested that absorptionwas delayed following injections below the level of injury. Inall three cases the elimination rate constant was smaller, thehalf-life longer, and the volume of distribution larger followinginjections below the level of injury. In addition, thelogarithmic plotting of serum levels following injections inparalyzed muscle was non-linear, adding further support to thesupposition that absorption was delayed.With a sample size of three, conclusions are tentative. Thefindings suggest that peak and trough serum levels may be greaterfollowing injections above the level of injury as compared tobelow if the dosing interval is every 12 hours and steady stateis achieved prior to serum samples being drawn. Given possibledelayed absorption from paralyzed muscle, shortened dosingintervals may result in drug accumulation.The results of this study have implications for practicerelated to I.M. site selection, dosing levels, and serum levels.Education for health professionals must address innervation as apossible influence on I.M. drug absorption. This study providesinsight into areas for further refinement of the theoreticalframework as well as areas for further research.Table of ContentsPageABSTRACT^LIST OF TABLES^  viLIST OF FIGURES  viiACKNOWLEDGEMENTS^  viiiCHAPTER ONE: INTRODUCTION^  1Introduction  1Background to the Problem  1Problem Statement  3Purpose^  3Theoretical Framework^  3Drug Action^  5Diffusion Area  5Blood Flow  5Hypotheses  7Definition of Terms^  7Significance^  9Overview of Thesis Content^  10CHAPTER TWO: REVIEW OF THE LITERATURE^ 11Introduction^  11Serum Drug Absorption^  11Drug Action  14Drug Properties  14Interacting Drugs  14Area for Diffusion^  15Needle Size  15Massage^  16Withdrawal Technique  16Blood Flow  16Renal and Cardiovascular Function^ 17Muscle Group^  17Muscle Innervation^  18Spinal Cord Injury and Drug Absorption^ 19Summary^  22CHAPTER THREE: METHODS^  24Introduction  24Research Design  24Sample Selection and Sample Criteria^ 26Assumptions^  27Limitations  27Data Collection Instruments^ 27Abbott TDX  27Data Collection Tool  29Data Collection Procedure  29Protection of Human Rights^  31Data Analysis^  32Summary^  33ivPageCHAPTER FOUR: PRESENTATION AND DISCUSSIONOF RESULTS^  34Introduction^  34Characteristics and Discussion of Results ^ 34Sample  34Influencing Factors^  35Nev Laboratory Protocol^ 35Concurrent Research Study  36Nev Antibiotics  37Findings and Discussion of Case Studies^ 38Case 1^  38Case 2  45Case 3  53Case 1-3  59Summary^  62CHAPTER FIVE: SUMMARY, CONCLUSIONS ANDRECOMMENDATIONS  64Introduction^  64Summary  64Conclusions  68Implications  70Recommendations for Further Research^ 73REFERENCES^  76APPENDICESA. Consent Form^  79B. I.M. Injection Procedure^ 81C. Data Collection Form  85D. Venipuncture Procedure  90E. Calculations for PharmacokineticParameters^  92F. Concurrent Research Study^ 94List of Tablesv iPageTable 1. Subject 1 - Comparative Serum Levels^ 39Table 2. Subject 1 - Pharmacokinetic Values 43Table 3. Subject 2 - Comparative Serum Levels^ 47Table 4. Subject 3 - Comparative Serum Levels^ 54Table 5. Subject 3 - Pharmacokinetic Values 57List of FiguresFigureFigure1.2.Intramuscular Absorption Framework^Serum Drug Absorption FollowingIntramuscular Injection^Page412Figure 3. Study Design^ 25Figure 4. SubJect 1 - Serum ConcentrationTime Curve 40Figure 5. Subject 1 - Logarithm of Serum LevelsVersus Time^ 44Figure 6. SubJect 2 - Serum ConcentrationTime Curve 48Figure 7. Subject 2 - Logarithm of Serum LevelsVersus Time^ 51Figure 8. Subject 3 - Serum ConcentrationTime Curve 55Figure 9. Subject 3 - Logarithm of Serum LevelsVersus Time^ 58viiACKNOWLEDGEMENTS^ viiiThis thesis is dedicated to my husband for giving me thecourage to believe in my capabilities, and whose unfailingsupport and encouragement have carried me through to thecompletion of this thesis.i xACKNOWLEDGEMENTSI would like to thank the members of my thesis committee, Dr.Ann Hilton (chairperson) and Marilyn Dewis for sharing theirexpertise and providing guidance and support.The pharmacological expertise provided by Marilyn Boyce,M.Sc. Pharm. and Terri Betts, B.Sc. Pharm. was invaluable, as wasthe assistance that Dr. W. B. Boldt provided in analyzing thedata.I would like to thank the research assistants, Lorna DickR.N., Colleen Powers R.N., and Anna Krzyzanavoski R.N. whodiligently collected the data for this study.My appreciation is extended to the nursing staff andphysicians on the spinal cord injury service at therehabilitation centre where the study was conducted. Sincerethanks are also extended to Dr. Gribble for her efforts inidentifying potential subects.I am grateful to the British Columbia Rehabilitation Societyfor their financial assistance.Finally, I would like to thank the patients who participatedin this study.1CHAPTER ONEIntroductionbackground to the Problem,It is estimated that there are 150,000 spinal cord injuredpersons in North America, and that each year approximately 10,000more are injured (Martin, Holt & Hicks, 1981). Annually inBritish Columbia, approximately 130 persons suffer a spinal cordinjury (Canadian Paraplegic Association, 1989). There is amultitude of physical and psychosocial consequences of spinalcord injury. Physical impairments include loss of motorfunction, loss of sensation, alterations in sexual relationships,and loss of bowel and bladder control.Loss of bladder control places the individual at high riskfor the complication of bladder infection because of the need forrepeated catheterizations (Trieschmann, 1982). According toMartin, Holt, and Hicks (1981), the greatest incidence ofmorbidity and mortality in the spinal cord population occursbecause of infections of the urinary tract. Serious infectionsdue to gram-negative organisms are often treated withintramuscular (I.M.) or intravenous (I.V.) gentamicin (Goodman &Gilman, 1981). For clients in the community or in non-acuterehabilitation settings such as the centre participating in thisstudy, intramuscular therapy is preferable to intravenous therapyas it does not require admission to an acute care facility.In general, physicians at the participating centre prefer toorder a medication be given I.M. rather than I.V., but practiceis mixed when it comes to ordering gentamicin in the spinal cordinjured population. The majority of physicians order gentamicin2I.M. but a few physicians suspect that gentamicin given by theI.M. route is not as effective in the spinal cord injuredpopulation as compared to the general population. Although thesephysicians have not been able to validate their suspicions, ithas influenced their practice. They tend to order gentamicin begiven I.V. rather than I.M. when it is indicated as the drug ofchoice for persons with a spinal cord injury. (Medical staffinterview, 1989). Although physicians choose the route of drugadministration, it is the nurse who selects the site.When I.M. administration of medication is prescribed forpatients with a spinal cord injury, the nurse selects from arange of possible sites. Administration below the level of theinjury where there is loss of sensation generally provides apain-free injection, whereas administration above the level ofinjury is likely to cause slight discomfort. Administrationbelow the level of injury is the most frequent choice accordingto a survey of approximately 30 registered nurses, working withpatients with spinal cord injuries (Spurrell, 1989). Althoughadministration below the level of the injury is more comfortablefor the patient, there is perhaps a more important factor toconsider in site selection. With paralysis there is some tone inthe smooth muscles of the blood vessels, but this cannotcompensate for the flaccidity of the skeletal muscles, resultingin reduced blood flow in paralyzed tissue (Guttman, 1974;Seifert, 1972). Administration of I.M. medication to these siteswould therefore likely influence drug absorption (Segal, 1988).Now influential this factor is in site selection has not beenstudied in the spinal cord injured population.3Problem StatementAlthough we have information to suggest that injections belowthe level of spinal cord injury are not absorbed as well as thosesame sites on able-bodied persons (Segal, 1988), no research wasfound which compared absorption levels above and below injurysites. The question arises, would gentamicin absorption inspinal cord injured patients be improved if nurses gaveintramuscular injections in "normal" rather than paralyzedmuscle?Since nurses are the prime caregivers and persons responsiblefor I.M. site selection, information which helps to clarify thebest sites in persons with a spinal cord injury would assist thenurse to make decisions that would produce the best drug effect.The current nursing literature offers no direction regarding I.M.injections in the spinal cord injured population (Dittmar, 1989;Sorensen & Luckmann, 1979; Martin, Holt, & Hicks, 1981).PurposeThe purpose of this study was to determine the difference indrug absorption between intramuscular injections given above andbelow the lesion in persons with a spinal cord injury, when thelesion is within the range of C-6 to L-2. Injuries within thisrange affect the gluteal muscle but not the deltoid muscle(Warwick, 1973).Theoretical FrameworkThe theoretical framework for this study focused on serumdrug absorption following intramuscular injections. It was acombined physiological and pharmacological framework whichidentified factors influencing serum drug absorption. Figure 11 Interacting Drugs^)7Drug Action IBlood Flow I^  Serum DrugAbsorptionDrug PropertiesI Diffusion Area I -I Needle Size4divides the factors into three broad categories - diffusion area,drug action and blood flow. Identified within each of thesebroad categories are a number of specific factors which influenceserum drug absorption following intramuscular injections.FIGURE 1 Intramuscular absorption framework reflecting factors influencingserum drug absorption with intramuscular injections.Withdrawal Technique5Drug Action The framework identified drug action as one of the threecategories of factors influencing serum drug absorption. Drugaction, and in turn serum drug absorption, is influenced by twofactors - individual drug properties and interacting drugs.Kock-Weser (1974) identified three individual drug propertiesknown to influence serum drug absorption - drug lipophilicity(ability to diffuse directly through the capillary wall), drugvolume and drug concentration. Interacting drugs can affectserum drug absorption by either enhancing or inhibiting drugactivity (Tindula, 1983).Diffusion Area According to the framework, surface area for diffusionaffects serum drug absorption. Three factors identified asinfluencing absorption by affecting diffusion area were needlesize, massage and withdrawal technique.Surface area, and thus absorption, can be increased byincreasing the depth of the injection with a longer needle andthrough massage of the area following injection (Zellman, 1961;Kock-Weser, 1974). The withdrawal technique can influencewhether all the medication remains in the muscle or some hasleaked into the subcutaneous tissue. In the latter case,absorption is slower (Zellman, 1961).Blood Flow Of the three categories of factors identified as influencingserum drug absorption, blood flow is known to have the primaryinfluence. Early studies suggested diffusion had the greatestinfluence, but a study by Bederka (1971) identified blood flow as6the key factor influencing the rate of serum drug absorption ofsubstances administered intramuscularly.The framework identified four factors which influence serumdrug absorption through their effect on blood flow. These fourfactors were renal function, cardiovascular function, musclegroup and muscle innervation. First, it was noted, with renaldysfunction there is a reduced ability to clear the drug from thesystem. This may make it appear as though absorption is enhancedby elevating the peak and trough serum levels (Ems & Norwak,1983). second, decreased cardiac output reduces blood flow.Conversely, increased cardiac output, such as occurs withexercise, increases blood flow (Emus & Norwak, 1983; Seifert,1972). Third, Evans (1975) found that blood flow varied indifferent muscle groups. The blood flow in the deltoid musclewas found to be faster than that of the vastus lateralis, whichin turn was found to be faster than blood flow in the glutealmuscle. Fourth, if muscle innervation is reduced, as occurs withparalysis, the tone and muscle mass decrease and blood flowbecomes reduced (Guttman, 1974).In summary, the framework identified three categories offactors influencing serum drug absorption with intramsucularinjections - drug action, area for diffusion and blood flow.Within each category there were specific factors identified asinfluencing absorption. This study focused on the influence thatmuscle innervation (paralysis) has on serum drug absorption. Ittested the theory that decreased muscle innervation decreasesblood flow, and thus decreases serum drug absorption.7HypothesesThe following hypotheses were tested in this study.1. The serum trough level of gentamicin, following I.M.injections, in persons with a spinal cord injury is greater whenthe injections are given above the level of injury than when theyare given below.2. The peak serum level of gentamicin, following I.M.injections, in persons with a spinal cord injury is greater whenthe injections are given above the level of injury than when theyare given below.3. The absorption time of I.M. gentamicin, in persons with aspinal cord injury, is shorter when injections are given abovethe level of injury than when they are given below.Definition of TermsThe theoretical and operational definitions of the termsaddressed in the hypotheses are described below. The termsaddressed include those pertaining to serum drug absorption andthose pertaining to spinal cord injury.Berum Drug Absorption Serum drug absorption refers to the amount of drug reachingthe systemic circulation (Winter, 1989).Operational Definition: Serum drug absorption was defined interms of the trough level, the peak level, and the absorptiontime.Trough Level The trough level was defined as the lowest level of drug in8the systemic circulation tug/ml) determined by taking ameasurement just prior to drug injection (Shlafer & Marieb,1989).peak Level The peak level was defined as the highest level of drug inthe systemic circulation (ug/ml) determined by taking the highestof the four measurements following drug injection.Absorption Time The absorption time was defined as the time required for allof the drug injected into the muscle to be absorbed into theblood stream. It was determined by measuring the time from druginjection until the peak serum level was achieved.Spinal Cord Iniury (lesion) Spinal cord injury referred to trauma to the spinal cordresulting in either temporary or permanent loss of motor and/orsensory function below the level of injury (Trieschmann, 1882).Operational Definition: For the purposes of this study spinalcord injury referred to a complete injury within the range of C-6to L-2 in which there was a complete loss of motor function belowthe level of injury. The injury was classified as a completeinjury regardless of sensory function.above the Level of Iniury Above the level of injury referred to that area of the bodyinnervated by segmental levels above the spinal cord lesion(Guttmann, 1974).For the purposes of this study, above the level of injuryreferred to a specific muscle unaffected by the spinal lesion -the deltoid muscle; the muscular cap of the shoulder.9Innervation for the deltoid muscle occurs at C-5 in the spinalcord (Williams, 1973).Below the Level of Injury Below the level of injury referred to those areas at or belowthe segmental level of the lesion; areas affected by motorparalysis (Guttmann, 1984).For the purposes of this study, below the level of injuryreferred to a specific muscle affected by motor paralysis - thegluteal (dorsal gluteal) muscle in the upper outer quadrant ofthe buttocks. Innervation for the gluteal muscle occurs at L-4in the spinal cord (Williams, 1973).SignificanceThis study was significant in terms of increasing the body ofknowledge in nursing as well as other disciplines such aspharmacology, medicine, and physiology. The theoreticalframework for this study indicated that reduced muscleinnervation (paralysis) reduces blood flow which decreases serumdrug absorption. This study tested that relationship, and thustested the theory.On a more concrete level the results of this study allownurses and other health care professionals to make more informeddecisions when working with spinal cord injured patients whorequire I.M. injections. Physicians have more information onwhich to base their decisions regarding route of administrationof gentamicin, or other medication which may be given I.M. orI.V., with spinal cord patients. Nurses have further data onwhich to base site choice when giving I.M. injections to personswith a spinal cord injury.1 0Regardless of whether the hypotheses were rejected oraccepted, this study contributed to the knowledge base in nursingand other health professions. Quality of patient care isenhanced when the best choices in terms of route and/or site ofgentamicin treatment for persons with a spinal cord injury areclarified.Overview of Thesis ContentThis thesis is comprised of five chapters. In Chapter One,the background to the problem, problem statement, purpose,conceptual framework, hypotheses, definitions and significance ofthe study were given. In Chapter Two, a review of selectedliterature presents the factors that affect serum drug absorptionwith intramuscular injections, followed by a critical review ofstudies which have focused on the specific influence of muscleinnervation (paralyis) on serum absorption of intramuscularinjections. In Chapter Three the research methods, including adescription of the research design, sample selection,assumptions, limitations, data collection instruments andprocedures, and ethical considerations and proposed statisticalprocedures to be used in data analysis are presented. ChapterFour begins with a description of the sample and a discussion offactors which may have influenced sample size. This is followedby a presentation of the results and discussion of these results.The summary, conclusions, implications and recommendations forfuture research are presented in Chapter Five.11CHAPTER TWOReview of the LiteratureIntroduction The literature relevant to this study can be viewed withinthe context of the theoretical framework presented in Figure 1.The review begins with an in-depth examination of serum drugabsorption and the three categories of factors influencingabsorption - drug action, surface area for diffusion, and bloodflow. This is followed by a critical review of studies whichhave focused on the specific influence of muscle innervation(paralysis) on serum absorption of intramuscular injections.$erum Drug Absorption Looking first at serum drug absorption, literature in thefield of pharmacology was consistent in its description of thisconcept. The terms peak drug level, trough drug level andabsorption time, or rate of absorption were generally used todescribe intramuscular absorption.As seen in Figure 2, the trough level is the lowest level ofdrug in the systemic circulation (Winter, 1989). The peak levelis the highest level of drug in the systemic circulationfollowing intramuscular injection. The absorption time refers tothe time from injection until the drug reaches the peak serumlevel (Winter, 1989).The three pharmacokinetic parameters - peak level, troughlevel and absorption time, offer a basic picture of drugabsorption. If indicated, additional parameters may becalculated for the absorption or elimination phase of a drug, toprovide a more complete picture of a drug's disposition.Absorption Phase Elimination PhasePeak LevelTroughLevel Absorption Tune -30112Figure 2. Serum drug absorption following intramuscularinjection. Adapted from Basic clinical Pharmacokinetics by M.Winter, 1989)Serum Level(ug/ml)Injection^TimeThe concepts of absorption phase and elimination phase aredepicted in Figure 2. The upward slope of the plotted serumlevels correlates with the absorption phase of the drug while thedownward slope correlates with the elimination phase of the drug.With drugs such as gentamicin, absorption is thought to becomplete by the time the peak is achieved. With this type ofdrug disposition, the elimination phase can be characterized byfirst-order elimination kinetics - "a process in which the amountor concentration of drug in the body diminishes logarithmicallyover time" (Winter, 1989, p. 383). Parameters used to measurethis type of elimination include elimination rate constant,half-life, and volume of distribution.13The intent of this study was to focus on the trough level,peak level, and time of absorption, but as necessary additionalcalculations were made to give a more complete picture of adrug's disposition following intramuscular injections.The desired/usual parameters for serum drug levels can befound in the literature. Using intramuscular injections ofgentamicin in healthy subjects as an example, the peaktherapeutic plasma concentration is in the range of 4-8mg/L(Winter, 1989). Therapeutic trough levels are less than 2 mg/L.Sustained trough levels higher than this have been associatedwith toxicity (Winter,1989). Winter notes that absorption timeis less predictable with I.M. injections than intravenous.However, in most patients gentamicin plasma concentrations peakapproximately one hour after an I.M. injection. Standards ofpractice in Vancouver seem to support this assumption. A surveyof the major hospitals in Vancouver indicated the laboratorieshave set a standard of one hour post I.M. injection for thecollection of all peak serum gentamicin levels. The pharmacologyliterature was not only consistent in the definition ofabsorption, but also in the levels and absorption timesidentified for specific drugs such as gentamicin.The theoretical framework for this study identified threecategories of factors which influence serum drug absorption. Thecategories of factors which were identified as having a potentialinfluence on the serum trough level, peak level, and/orabsorption time were drug action, area for diffusion, and bloodflow. What follows is a detailed description of each of thesecategories beginning with drug action.14Drug Action The framework identified drug action as one category offactors influencing serum drug absorption. This category can bedivided into influences on absorption related to drug properties,and influences related to interacting drugs.Drug Properties Drug properties which may affect absorption includelipophilicity, volume and concentration. Kock-Weser (1974)identified high lipophilicity as being associated with rapidabsorption. His findings indicated that drugs that are poorlywater soluble may precipitate at the injection site and becomeunable to diffuse into capillaries. Gentamicin is very watersoluble and is therefore absorbed well following intramuscularinjections (Winter, 1989).Drug volume and concentration have been identified asinfluencing the rate of absorption, but this relationship appearsto vary with different drugs as Jebson (1971) demonstrated. Hisstudy revealed that atropine is absorbed from muscle more rapidlywhen it is administered in a smaller volume of more concentratedsolution, whereas this did not hold true for lidocaine. Althoughnoted as an influence, generalizations about the effect of drugvolume and concentration on absorption cannot be made. Researchregarding the influence of volume and concentration of gentamicinon serum drug absorption was not found.Interacting Drugs In addition to drug properties, the literature indicated thatinteracting drugs may enhance or inactivate absorption. Onceagain using gentamicin as the example, it is noted that patient15serum samples which contain the drugs sagamicin, sisomycin andnetilimicin will yield falsely elevated values for gentamicin.High concentrations of penicillins or cephalosporins have beenshown to inactivate gentamicin in vitro (Tindula, 1983).It is clear from the literature that both drug properties andinteracting drugs may influence drug action and thus serum drugabsorption. In addition to being affected by drug action,absorption is affected by the surface area for diffusion.Area for Diffusion The theoretical framework (Figure 1) identified surface areafor diffusion as one of three categories of factors whichinfluence absorption. A frequently quoted article by Zellman(1961) reports research findings and case studies which provideinsight into the influence that three specific factors -needlesize, massage, and withdrawal technique - have on diffusion areaand thus absorption.Needle Size Needle size was identified as an important factor influencingabsorption. Zellman noted that if the length of the needle isnot sufficient to reach the "belly of the muscle" there is dangerof injection into subcutaneous tissue which results in slowerabsorption and greater tissue reaction. His findings suggestthat a needle must be no shorter than 1 1/2, and generally needsto be no longer than 2 1/2 inches. In addition to needle length,bore size is important. According to Zellman, a large bore sizeincreases the likelihood of subcutaneous leakage, and slowerabsorption.16Massage A second factor which was identified as influencing surfacearea for diffusion was massage. According to Zellman (1961) andKock-Weser (1974) deep, firm massage of the muscle tissue favorsspread of the medication through a wider area of tissue,increasing the area of absorption and decreasing the intensity ofdiscomfort.Withdrawal Technique Withdrawal technique was the third factor which wasidentified as influencing absorption by affecting the surfacearea for diffusion. Zellman reported that radiographs ofinjections reveal that quick withdrawal, without leaving theneedle in place for a few moments, and failure to apply immediatepressure result in subcutaneous leakage and thus slowerabsorption. Zellman suggested that 0.2 cc of air in the syringebarrel held upright provides the means for clearing the needle ofmedication before withdrawal, thus reducing subcutaneous leakage.In summary, the literature identified needle size, massage,and withdrawal technique as three factors influencing absorptionthrough their effect on surface area for diffusion. The nextsection addresses those factors known to alter absorption throughtheir effect on blood flow.Blood Flow The third, and most critical of the factors influencingabsorption, has been identified as blood flow. Testing the rateof absorption of a variety of compounds with different diffusioncoefficients, Bederka (1971) demonstrated that blood flow is themost critical factor affecting absorption from muscle. Blood17flow was altered through the absorbing site by adding drugs knownfor their vasoconstrictor and dilator effects. The significanceof this study is noted repeatedly in the literature.The framework for this study identified four factorsinfluencing blood flow - renal and cardiovascular function,muscle group and muscle innervation.Renal and Cardiovascular Function Blood flow is influenced by renal and cardiovascularfunction. The literature in the field of physiology supports thetheory that renal and cardiac dysfunction are both associatedwith reduced blood flow (Ernes & Nowak, 1983). In the case ofrenal dysfunction, drug excretion is hampered. Gyselynck andcolleagues (1971) studied the renal clearance of gentamicin in 18patients with different degrees of renal function. They foundthat in cases of severe renal failure the half life of gentamicinwas unusually prolonged. The half-life of a drug is the amountof time required for the plasma drug concentration to decrease byone-half (Winter, 1989). In a review article (1968) Ballardcited a number of studies which found that in the case of cardiacfailure the half-life was prolonged, and serum levels were lowerdue to reduced blood flow.muscle Group Blood flow is influenced not only by renal and cardiovascularfunction, but also by muscle groups. Evans (1971) demonstratedthat blood flow varies with different muscle groups by measuringthe resting muscle blood flow in normal subjects. She performedsimultaneous measurements in the usual intramuscular injectionsites in 20 subjects. Her findings indicated that the deltoid18muscle had the greatest blood flow, followed by the vastuslateralis, and the gluteal muscle. She found the differences tobe consistent and suggested they were of sufficient magnitude toaffect the rate of absorption and peak serum levels followingintramuscular administration of drugs. She noted, however, thatfurther study is needed to determine for which drugs thedifference has clinical significance.Muscle Innervation The final factor identified as influencing blood flow, andthus serum drug absorption was muscle innervation. A spinallesion blocks nerve pathways interfering with muscle innervation.Reduced innervation leads to muscle atrophy and flaccidity, whichin turn results in reduced blood flow in the paralyzed tissue(Guttman, 1974).Seifert and colleagues (1972) studied the blood flow inmuscles of paraplegic patients using a double isotope measurementtechnique. They compared blood flow in the normal bicep musclewith the paralyzed anterior tibial muscle. They concluded thatblood flow was significantly reduced in paralyzed muscle,however, no consideration was given to possible differences inblood flow in normal biceps versus normal anterior tibialmuscles.The literature supported the theory that renal andcardiovascular function, and muscle groups influence blood flowand absorption. Seifert's study was the only study found whichlooked at the relationship between muscle innervation and bloodflow. Although the results suggested a relationship they did notaccount for "normal" differences in blood flow in the biceps19versus the anterior tibial muscles. It is also unknown, fromthis study, whether the effect of muscle paralysis on blood flowwas significant enough to affect serum drug absorption followingintramuscular injection.Spinal Cord Injury and Drug Absorption There is limited literature on the effects of spinal cordinjury on drug absorption. Only three studies were found thatexamined I.M. administration of gentamicin in spinal cord injuredpatients. Segal, 1986, compared absorption of intramuscularlyadministered gentamicin in 17 spinal cord injured subjects tothat administered to 8 able-bodied control subjects. The studycontrolled for interacting drugs, cardiac function, renalfunction, and injection technique. Single injections were givenin the vastus lateralis of all subjects. Blood samples wereobtained and the serial time-course of serum gentamicinabsorption was followed. Pharmacokinetic parameters wereestimated from semi-logarithmic plots of serum drug concentrationversus time.Segal found that the mean peak serum level fug/ml) achievedwas higher in the controls (5.84 ± 1.14) than in the spinal cordinjured population (4.27 ± 0.68). He found that the meanabsorption time was 0.69 hours + 0.18 in the controls versus 1.1±0 .4 in the spinal cord injured population. In addition tofinding an increased absorption time and decreased serum peaklevel in the spinal cord injured group, Segal found thatelimination appeared to be delayed (decreased elimination rateconstant, increased half-life and increased volume ofdistribution). He suggested that the apparent delay in20elimination probably reflected the influence of a slowedabsorptive phase on the terminal elimination kinetics. Althoughhis findings appear significant, the study only examined serumlevels following one dose of gentamicin, and may not bereflective of the serum levels after repeated doses. Noindication was given as to why equal numbers of subjects were notincluded in the control group. The presumption that apparentdelays in elimination are related to delayed absorption isplausible but requires further study with more explicit controlfor factors which could influence elimination. In examining thechanges in gross body composition with spinal cord injuredpatients, Greenway and associates (1970) found thatpathophysiological changes such as alterations in motor tone andmuscle mass contributed to an increase in total extracellularfluid volume. It would be difficult to identify what portion ofthe delay in elimination was attributable to slowed absorption,and what was attributable to an increase in volume ofdistribution as a result of an increase in extracellular fluidvolume.A more complex follow-up study was done by Segal in 1988. Inthis study paraplegics, tetraplegics and able-bodied subjectsreceiving I.M. and I.V. gentamicin were compared. The subjectswere divided into: I.M. only, I.V. only, and a cross-over group.In this study Segal looked at both the rate and completeness ofgentamicin absoption. He found that the amount of drug reachingthe systemic circulation was undiminished in able-bodied andspinal cord injured subjects regardless of whether the drug wasadministered intramuscularly or intravenously. While Segal found21that the completeness of absorption was not affected by spinalcord injury, he duplicated his earlier findings which suggestedthat rate of absorption is altered in spinal cord injury. Hefound, once again, that I.M. gentamicin was absorbed more slowlyand the peak level reached was lower in spinal cord injuredpatients than in the "normal" population. In this study, as inthe previous one, he linked a delayed elimination half-life to aprolonged absorption phase following injections in paralyzedmuscle. Further support was given to this proposition by thesemi-logarithmic plotting of the absorption profiles. Segalfound that the profile for the spinal cord injured group was notlinear, suggesting that for this group absorption may not be asimple first order process.The final study found was done in India by sankaranarayananand associates in 1989. In this study the I.M. absorption ofgentamicin from the deltoid muscle was compared using sixbed-ridden paraplegics and six able-bodied subjects. The studycontrolled for a number of factors known to influence absorptionsuch as: cardiac function, renal function and hepatic function,but no mention was made as to whether there was any control forinteracting drugs.The study found that the peak serum level was lower and thetime to reach the peak was delayed following injections in theparaplegics as compared to the controls. The authors recognizedthat the results could possibly by attributed to the increasedvolume of distribution seen as a result of pathophysiologicalchanges associated with spinal cord injury. The authors alsosuggested that in paraplegics who are bedridden, as is the case2 2in India, there may be a generalized decrease in muscle bloodflow contributing to impaired absorption from non-paralyzedlimbs. To test this the authors would need to repeat the studywith a control group made up of persons with intact neuraxis whoare bedridden - not an easy group to find.SummaryIn summary, serum drug absorption was discussed in theliterature using pharamacokinetic parameters such as serum troughlevel, peak level, and absorption time/rate. In additioninformation about drug absorption/elimination was described inthe literature using parameters such as elimination rateconstant, half-life and volume of distribution.The literature supported the theory that drug action, surfacearea for diffusion and blood flow influence serum drug absorptionfollowing intramuscular injections. In addition the literaturesupported the specific factors identified within each of thesethree broad categories of influence.There were relatively few studies exploring the absorption ofI.M. gentamicin in the spinal cord injured population. Twostudies found suggest that gentamicin is not absorbed as well inthe spinal cord injured population as in the "normal" populationwhen injections/infusions are given below the level of injury.One study found that absorption was impaired in non-paralyzeddeltoid muscle of bedridden spinal cord injured patients ascompared to deltoid injections in an able-bodied control group.This study needs to be replicated in active paraplegics beforeany generalizations can be made. No studies were found thatcompared absorption above and below the lesion in spinal cord23injured patients. This leads one to question if absorption wouldbe improved if injections were given above the level of injury,in non-paralyzed muscle where the blood flow is greater. Thisstudy was designed to test this hypothesis.24CHAPTER THREEMethodsIntroduction This chapter provides a description of the methods used tocompare intramuscular injections above and below the level ofinjury. Content includes a discussion on the research design,sample selection and criteria, assumptions and limitations, datacollection instruments, data collection procedures, proceduresfor protection of human rights and data analysis.Donign This study used an experimental, repeated measures designwith counterbalancing (Figure 3). The subjects acted as theirown controls by receiving injections both above and below thelevel of spinal cord injury. The initial site of medicationinjection was randomly assigned. Before and after the fourthmedication injection in each site, serum samples were drawn todetermine comparable trough levels, peak levels, and absorptiontimes. Choosing to draw blood samples before and after thefourth dose was based on the fact that steady state is achievedby the third dose (Winters, 1989). Figure 3 illustrates thesequence of events.Five serum gentamicin samples were taken at each site. InFigure 3, subject 1, X represents injections in the deltoidmuscle. Just prior to the fourth injection, a serum sample wastaken (01). According to Winter (1989) serum trough levelsshould be obtained within the half hour prior to the next dose.25Figure 3. Study design illustrating sequence of injections andserum samples.Subject order^Treatment Sequence1. R X1-3 01 X4 02-5 Y1-3 01 Y4 02-52. R Y1-3 01 Y4 02-5 X1-3 01 X4 02-510.Symbol Guide R = random assignmentX = above lesion injections (deltoid)Y = below lesion injections (gluteal)0 = measurement of serum gentamicinFurther samples were taken at 1, 2, 3, and 4 hours post injection(02 - 05). These times were determined in consultation withclinical pharmacologists. Because the hospital researchcommittee specified that no more than four samples could becollected post medication injection, the times were spaced inorder to provide a picture of both the absorption and eliminationphases of the drug.Once the five samples were collected the site was changed andthe entire process repeated. This means that, for subject 1 inFigure 3, just prior to the fourth injection in the glutealmuscle (Y4) a serum sample (01) was drawn, followed by samples at1,2,3, and 4 hours post-injection (02-5). Once the 10 sampleswere collected, the site of any remaining injections was of no26significance to this study.Bample selection The target population of this study was persons with spinalcord injuries between the levels of C-6 and L-2 with completeloss of motor function below the level of injury. A conveniencesample of 10 patients from one rehabilitation centre was to beselected based on the following criteria:1. All subjects had a gram negative bladder infection whichtheir physician had determined was best treated with I.M.gentamicin.2. All subjects had a physician's order for I.M. gentamicin fora minimum of four days in equally divided doses over equal timeintervals. The dosage and time interval between injections wereindividually calculated. Between patients there were varyingdosages and time intervals, but individual treatment regimes wereto remain constant.3. All subjects had no clinical or laboratory evidence ofhematologic, cardiac, renal or hepatic disease.4. During the two weeks prior to being in the study none of thesubjects received any drugs known to alter muscle blood flow,influence gentamicin disposition, or interfere with assaymethods.5. All subjects were diagnosed as having a complete spinal cordinjury (no motor function below the level of injury), in therange of C-6 to L-2.6. All subjects had signed written informed consents(Appendix A).While it was the intention of this researcher to have asample size of 10, after a year and a half of data collection,27the actual sample size was only three. Possible explanations forthe lack of subjects are detailed in chapter four.Assumptions It was assumed that I.M. injections are preferred over I.V.therapy.It was assumed that there was no cross-over of gentamicinfour doses after the site change, based on known renal clearancetimes for gentamicin. (Winter, 1989).Limitations The major limitation of this study was that of the samplesize, which was dependent upon the frequency of patients beingdiagnosed with a gram negative bladder infection best treated byI.M. gentamicin, during the length of time feasible for thestudy. The actual sample size had to be reduced to three fromthe proposed 10.The I.M. injections were given by a number of nurses.Although they were all following a set procedure (Appendix 8)there may have been minor variations in technique.Limits placed on the number of serum samples which could becollected, restricted the types of pharacokinetic parameterswhich could be calculated.pata Collection Instruments The two instruments that were used to collect the data inthis study included an Abbott TDX and a data collection sheet.Abbott TDX In this study the serum gentamicin levels were measured bymeans of fluorescence polarization amino assay. The specificinstrument used was the Abbott TDX. Watson and colleagues28(1976), reported that serum gentamicin results by florescencepolarization correlate with both bioassay (r= 0.93) andradioimmunoassay (r= 0.97) methods of analysis. Results whichcorrelate this highly with two well established methods ofanalysis suggest the Abbott TDX is a valid tool to use inmeasuring serum gentamicin.The accuracy and reproducibility of this instrument have beenthe subject of a number of studies in recent years. Comparisonsof bioassay, enzyme multiplied immunoassay and fluorescencepolarization immunoassay identified the latter as the mostaccurate (Araj et al., 1985). Cheng, Lam & French (1987) did acomparative evaluation of the Abbott TDX, the Abbott ABA200 andSyva LAB5000 for assay of serum gentamicin. They found all threeproduced a high degree of accuracy and reproducibility withspiked samples when the concentrations of gentamicin were withinthe range of 3-8 mg/l. However, with concentrations below 2 mg/1or above 8 mg/1, only the TDX system gave acceptable coefficientsof variation and accurate recoveries. With 10 repeated samples,and control gentamicin values of 1, 4, and 8 ug/ml, the TDXdetermined the levels to be 0.99 + 0.08; 4.04 + 0.15; and 7.91+0.11 respectively. As the results indicate, the Abbott TDX is areliable tool for measuring serum gentamicin.According to the users' manual, the Abbott TDX is sensitiveto a level of 0.3 ug/ml. This means that 0.3 ug/mi is the lowestmeasurable level of serum gentamicin that can be distinguishedfrom zero with 95% confidence. The laboratory used for thisstudy makes no distinction between gentamicin levels ranging fromzero to 0.3 ug/ml. Any levels within this range are reported as29< 0.3 ug/ml.The Abbott TDX has been well tested and is currently in usein over four hundred institutions in Canada. The accuracy of theAbbott TDX is measured in terms of accuracy by recovery. Byadding clinically relevant concentrations of gentamicin togentamicin-free pooled human serum and doing replicate assays onedetermines the average recovery. The user's manual for theAbbott TDX identifies the average recovery as 99% + 3.5%. Chenget al (1987) found similar results, confirming the validity ofthe tool.The serum testing for this study was done by a major teachinghospital where the instrument is part of a blind quality controlprogram and precision testing is done on a daily basis.Data Collection $heet The data collectors recorded relevant information pertainingto the patient's current health status, recent lab values, andspecific information related to gentamicin injections and serumsample collection. Recording was done on the data collectionsheet which is shown in Appendix C.pata Collection Procedure Prior to beginning the study, the investigator met with allof the rehabilitation centre physicians caring for patients withspinal cord injuries to explain the study and ensure theirsupport.All Registered Nurses who could have been involved in givingthe injections were given inservice preparation by theinvestigator to ensure standardization of the injection technique(Appendix B). The critical injections were those administered30just prior to the observations. To decrease the risk oftechnique variance, the critical injections were given by one ofthree nurses who acted as research assistants to the study.These three nurses were given more extensive preparation.In addition to giving the critical injections, the assistantswere responsible for drawing the serum samples. The assistantswere Registered Nurses experienced in venipuncture. Theinvestigator reviewed the venipuncture procedure with thesenurses (Appendix D) to ensure standardization of technique.When gentamicin I.M. was ordered for a patient, the pharmacydepartment informed the investigator. If the patient met thecriteria, the nurse clinician asked his permission to beapproached by the investigator. If the patient agreed toparticipate, an informed consent was signed (Appendix A). Thepatient's physician, and other staff who were affected by thestudy were notified.The individual patient doses were labelled according to date,time, dose and site. Nurses were made aware of the importance offollowing the exact directions. These same parameters were notedon the medication sheet, and in the Kardex. The samples wereanalyzed at a hospital laboratory and the results returned to theinvestigator.31protection of Human Rights The proposal was approved by the University of BritishColumbia Clinical Screening Committee for Research and OtherStudies Involving Human Subjects and by the Research ReviewCommittee at the participating rehabilitation centre.Potential subjects were given an information letter (AppendixA). If they agreed to be in the study a signed consent wascompleted. For the one subject who was unable to sign his ownname, due to impaired motor function, a witnessed 'X' satisfiedthe criteria for a signed consent. Parental consent was obtainedfor the one subject under the age of 19. Subjects were assuredin writing that they could withdraw from the study at any timeand that such action would in no way jeopardize their care.If any of the serum levels appeared above the therapeutic or"safe" level, the subject's physician would have been notifiedimmediately. Subject names did not appear on any of the writtendocumentation resulting from the study. Subjects were informedin writing that all results were confidential with the aboveexception.Burns and Grove (1987) would define this study as one of"minimal risk" as it caused temporary discomfort, but thepotential benefits outweighed the risks. Temporary discomfortcame from injections given above the level of injury where thesubject had sensation. It must be noted that the injectionswould have been given regardless of study participation; it wasonly the site of injection that was being manipulated. Thevenipunctures required to test serum gentamicin levels alsocaused temporary discomfort. It is usual practice for physicians32to order the collection of two serum gentamicin levels during aperiod of treatment. This study required patients to have anadditional eight samples collected (2ml/sample).Data Analysis If there had been 10 subjects, it was the intent of thisinvestigator to analyze the data using descriptive statistics andto test the hypotheses using one-tailed t-tests for dependentsamples. Descriptive statistics would have been used to detaileach of the serum drug measures - trough level, peak level andabsorption time - for each site. The mean level/time and thevariance would have been calculated for each parameter and eachsite. To test the hypotheses a one-tailed t-test would have beenused; one-tailed because the literature suggested that glutealabsorption would be slower/longer. Given 10 subjects the powerof such a test would have been approximately 0.7 if a 0.05 levelof significance was used.Because the sample size of 10 was not obtained, an alternatemethod of analysis was required. It was the learned opinion ofthe consultant statistician that given a sample size of three,the results were most appropriately viewed as three individualcase studies. Kennedy (1979) notes that one of the advantages ofcase analysis is the greater degree of detail which can beprovided for the reader. To provide more detail about serum drugabsorption, in each of the cases in this study, additionalpharmacokinetic parameters were calculated. In addition tocalculating the serum trough level, serum peak level, andabsorption time, the elimination parameters of elimination rateconstant, half-life, and volume of distribution were calculated.33(see Appendix E for definitions and equations). Furtherinformation about serum drug absorption was gleaned by graphingthe logarithm of the serum levels for each site.SummaryThis chapter has described the methods intended for use incomparing intramuscular absorption above and below the level ofinjury in persons with a spinal cord injury. The study wasdesigned as an experimental repeated measures design withcounterbalancing. The sample was to consist of a conveniencesample of 10 subjects who met the criteria - in actuality thesample consisted of three subjects. An overview of theassumptions and limitations of this study were presented. Theinstruments used to collect the data included an Abbott TDX and adata collection sheet. Three nurses, trained by theinvestigator, collected the data. The proposal was approved bythe UBC Clinical Screening Committee for Research and OtherStudies Involving Human Subjects and the Research ReviewCommittee at the particpating rehabilitation centre. It wasproposed that the hypotheses be analyzed using descriptivestatistics and t-tests, but given the reduced sample size theanalysis method was changed to case analysis.34CHAPTER FOURPresentation and Discussion of ResultsIntroduction This chapter is divided into two sections. The first sectionincludes a description of the sample and a discussion of factorswhich may have influenced the sample size. The second section isa presentation of the case studies with subsequent discussion ofthe findings.Characteristics and Discussion pf Sample Although the original plan to have a sample of 10 subjectswas considered reasonable based on the information available in1988-90, it was only possible to recruit four subjects into thestudy and have complete findings for three of these subjectsduring the data collection period which lasted from July 1990 toSeptember 1991. Possible factors contributing to a smallersample size included a new laboratory protocol, a concurrentresearch study and availability of new antibiotics. Each ofthese factors will be presented and efforts taken to increase thesample size will be described.Sample During the period of data collection for this study onlyseven patients with spinal cord injury were ordered gentamicin.Of the seven patients ordered gentamicin, one refused toparticipate in the study. Two of these patients did not meet thestudy criteria with regards to paralyzed and non-paralyzed muscle- One had been injured at C-4 resulting in paralyzed deltoid andgluteal muscle and the other had an incomplete injury with intactgluteal and deltoid muscles. Another patient was started on the35study, but due to a high fever he was transferred to acute carefor intraveneous antibiotics. The remaining three patients, whowere ordered gentamicin, made up the subjects for this study.possible Factors Influencing Sample Size Information was collected during the preparation of theresearch proposal to ensure that there would be sufficientpotential subjects who met the criteria. For the two years priorto the data collection, there were approximately 30 patients peryear at the Centre with spinal cord injury who were orderedgentamicin. During the 14 months of data collection however,only seven patients were ordered gentamicin.After 10 months of data collection, in an effort to increasethose eligible for participation, the medication choice wasextended to include amikacin and tobramycin. Like gentamicin,these drugs are in the aminoglycoside family and follow firstorder kinetics. The expansion of inclusion criterion did notcontribute to a larger sample size. Factors which probablyinfluenced this drop in potential subjects include a newlaboratory protocol for urine cultures, a concurrent researchstudy involving the same subjects, and new antibiotics on themarket.New laboratory protocol. It is likely that a change inlaboratory protocol resulted in fewer patients within theparticipating centre being ordered gentamicin. The protocol wasinitiated to reduce time and cost related to processing urinespecimens on asymptomatic patients. After June 1990 urinespecimens for culture and sensitivity would only be analyzed if"significant bacteriuria" was present. The criteria for analysis36was based on a minimum number of colony forming units per litre(CFU/L) and in some cases on the presence of specified clinicalsymptoms.While the pre-requisites were eased in April 1991, the policyappeared to have a significant impact on the number of patientshaving urine specimens analyzed. This in turn probably reducedthe number of patients being diagnosed as having a urinary tractinfection, and thus the number being treated withaminoglycosides. To illustrate the difference, a comparison wasmade between the number of urine specimens collected in the threemonths prior to the policy being implemented with the same threemonths period after it was implemented. The average number ofspecimens dropped from 30/month to 8/month - a 75% reduction,while there was no decrease in the number of patients with spinalcord injuries in the Centre. Although it is beyond the realm ofthis study to unequivically establish the impact of the newlaboratory protocol - it appears to be a possible factor whichinfluenced the sample size of this study. A second possibleinfluence was a concurrent research study.Concurrent research study. At approximately the same time asthis study began and the laboratory set up the new protocols, aconcurrent urinary research study on spinal cord injured patientswas being conducted at the same rehabilitation centre.^Subjectsfor the concurrent study were those persons with a neurogenicbladder as a result of spinal cord injury who were about to beput on intermittent catheterization. A majority of the spinalcord population were involved in this study. Subjects wererandomly assigned to one of two groups, A and B. Those in group37A received standardized antimicrobial therapy for all episodes ofbacteriuria (BU), whether symptomatic or asymptomatic, (seedefinitions in Appendix F). Those in group B were only treatedfor "symptomatic" bacteriuria.There are two ways that the concurrent study may haveinfluenced the sample size for the present study. Firstly,utilizing standardized treatment protocols may have decreased thesubjects' exposure to a range of antibiotics, thus decreasing thepossibility of resistances developing. The Centre pharmacistindicated that if the subjects had infections which remainedsensitive to oral antibiotics they would not require gentamicinfor gram-negative infections.Secondly, half of the subjects (those in Group B) were onlytreated for "symptomatic" bacteriuria.^Regardless of the numberof colony forming units per litre, this group was only treatedfor specific symptoms identified in Appendix F. Symptoms whichhad previously been considered grounds for treatment such asdysreflexia, reflex sweating, increased spasticity, malaise,urinary incontinence, and cloudy urine, were labelled asnon-specific symptoms in this study and were not to be treated.By restricting half of the subjects to treatment only for limitedsymptoms, there was a decrease in the possible use of gentamicin.New Antibiotics. The recent development and release ofquinolone drugs on the market is the third factor which probablyaffected the sample size of this study. While the use ofaminoglycosides decreased in the participating centre in the pastyear, the use of quinolones increased dramatically.Two quinolines currently on the market are norfloxacin and38ciprofloxacin, Quinolones are effective against gram negativebacteria, but unlike the aminoglycosides they can be given orallyand are therefore preferable (Winslade, 1991). The combinationof factors - change in laboratory protocol, concurrent researchstudy, and the marketing of quinolones, appeared to have had amajor effect on the sample size for this study.Findings and Discussion of Case studies Originally it was the intent of this investigator to analyzethe data using descriptive statistics and hypotheses testingusing one-tailed t-tests for dependent samples. Due to a finalsample size that was smaller than originally intended, theresults were more appropriately viewed as individual case studies(Boldt, 1991). To consider the subjects as cases requires one toemploy a replication rather than sampling logic. When employingreplication logic, it is appropriate to look at clinical ratherthan statistical significance (Yin, 1989). Each case wasconsidered akin to a single experiment which had been replicated.Findings for each of the three subjectsis presented and discussedboth individually and jointly.Case 11 The first case involved a 29 year old male who suffered acomplete spinal cord injury at T-12 six weeks prior toparticipating in the study. He weighed 56.5 kg and wasapproximately 5'10" with a muscular build. A previously healthyperson, he met the criteria for the study. Gentamicin wasordered when it was presumed he had pyelonephritis. His symptomsincluded fever, malaise, and lower abdominal discomfort. Thephysician ordered 80 mg. of gentamicin I.M. ql2h. The subject39was randomly assigned to receive the first four injections in thegluteal muscle and the subsequent four in the deltoid. The firstset of serum samples were obtained before and after the fourthinjection, and the second set of serum samples were obtainedbefore and after the eighth injection. The protocols forinjections and data collection were followed. Table 1 identifiesthe serum levels obtained following injections in each site, andFigure 4 visually displays the findings.Table 1Bublect 1 - comparative Serum Levels Serum Levels FollowingSite Specific InjectionsTime Deltoid Muscle^Gluteal Muscle1/2 hr. pre-injection^0.5ug/m11 hr. post injection^4.2ug/ml2 hr. post injection^3.2ug/ml3 hr. post injection^2.3ug/ml4 hr. post injection^1.7ug/m1<0.3ug/m13.8ug/ml2.8ug/ml2.0ug/m11.6ug/m1The results can be viewed in terms of supporting/rejectingthe three hypotheses of this study. The first hypothesis wasthat the serum trough level would be greater when the injectionsare given above the level of injury than when they are givenbelow. The trough serum level 1/2 hour pre-injection, (<0.3ug/ml.) was lower following injections in the paralyzed glutealmuscle, than the trough level of 0.5 ug/ml in the non-paralyzedpointofinjection Deltoid SiteTime3 hr. post1 hr. post 2 hr. post 4 hr. postFigure 4. Subject #1 - Serum Concentration Time CurveSerum Levels(ug/ml.)4.543.532.521.510.501/2 hr preTime Deltoid Glutold1/2 hr. pre 0.5 <.3I he. post 4.2 3.82 hr. post 3.2 2.83 hr. post 2.3 2.04 hr. post 1.7 16Gluteal SiteCVOSSM41deltoid muscle. These findings support the first hypothesis.The peak serum level, the highest of the four post injectionmeasurements, was 3.8 ug/ml following injections in the paralyzedmuscle as compared to 4.2 ug/ml following injections in thenon-paralyzed muscle. This supports the second hypothesis thatthe peak serum level would be greater when the injections aregiven above the level of injury than when they are given below.In the literature review it was noted that the therapeuticrange for gentamicin was 4-8 ug/ml. In case #1, while theinjections in the deltoid muscle reached a therapeutic level, theinjections in the gluteal muscle did not. According todiscussions with a clinical pharmacist working with spinal cordinjured patients, a peak level of 3.8 ug/ml, as was the situationfollowing the gluteal injections, would lead her to recommendthat the gentamicin dosage be increased. On the other hand shestated that if she was shown a peak level of 4.2 ug/ml, as wasthe case following deltoid injections, she would recommend thedosage not be changed. It is evident that the choice ofinjection site in this case could have affected the recommendedtreatment protocol.The third hypothesis was that the absorption time/rate ofI.M. gentamicin is faster when injections are given above thelevel of injury than when given below. In examining Figure 4 itappears that the absorption time was one hour for both sites.Unfortunately with limited serum samples it was not possible tospecify the exact time that the serum levels peaked and thereforenot possible to make conclusive statements regarding any possibledifferences in the absorption times without doing further42pharmacokinetic calculations.Given limited data about serum levels during the absorptionphase, indirect inferences regarding absorption times/rates camefrom the calculation of three elimination phase pharmacokineticparameters - the elimination rate constant, the half-life, andthe volume of distribution.Determination of these parameters required the drug to havereached steady state. According to Winter (1989) steady state isachieved by the fourth injection. Since levels were drawn afterthe fourth and eighth injections, in this case, one could assumethe drug was at steady state.Calculation of these parameters required two serum measures.The half hour pre-injection and one hour post-injection levelsare generally used, although using any measure for the trough isacceptable as long as the time between serum levels spans atleast one half-life (Winter, 1989, p. 44). In case #1, with atrough level of questionable accuracy (<0.3), it was moreappropriate to use the one and four hour post injection levelsfor the calculations. Having two serum levels drawn at steadystate allowed the following elimination phase pharmacokineticparameters to be calculated.In this case injections in the gluteal muscle resulted in asmaller elimination rate constant, a prolonged half-life and anincrease in the apparent volume of distribution as compared tovalues following deltoid injections. Generally these findingswould suggest that elimination was delayed following glutealinjections, but in this case it is likely that the differenceswee attributable to a prolonged absorption phase rather than43Table 2Bubiect 1 - Pharmacokinetic Values Parameters^ Deltoid Site Gluteal SiteElimination Rate Constant^0.30h-1^0.29h-1Half Life^ 2.3 hours^2.4 hoursVolume Distribution^14.5 litres^16.3 litresdelayed elimination.^Using the subject as his own controleliminated many factors which could have influenced elimination.Gentamicin is nearly totally eliminated by the kidneys, andgiven that during the time of data collection this subject had noapparent changes in renal function or fluid volume it seemsunlikely that the differences were a result of delayedelimination.Gentamicin is thought to be characterized by first-orderelimination kinetics, meaning that absorption is complete at thetime the peak is reached, and the drug diminishes logarithmicallyover time. Since the drug concentration diminisheslogarithmically, a graphic plot of the logarithm of the plasmalevel versus time should yield a straight line. In Figure 5,while the logarithm for the deltoid site appears linear, the samecannot be said for the gluteal site. This suggests that theelimination was not of the first order. Given that the subjectacted as his own control, and there was no apparent change inrenal function, it is likely the non-linear logarithm reflected aprolonged absorption phase rather than a delayed eliminationDeltoid SiteGluteal SitentniCynnW:Time Deltoid Glutold .1/2hr. pee 0.5 c31 hr. post 4.2 392 hr. post 3.2 2.83 hr. pon 2.3 2.04 hr. post 1.7 1.6Time Post-injectionFigure 5. Subject #1 - Logarithm of Serum Levels vs Time51n4Eao 3OO'E" 2bA01 hr^2 hrs^3 hrs^4 hrsdab45phase.In terms of whether one site created more discomfort than theother site, this subject described the injections in the deltoidas painful. He stated that it felt like "a pulled muscle for afew days", and slowed down his ability to wheel his chair. Nodiscomfort was noted with gluteal injections.In summary, in case #1 the serum trough and peak levels werehigher following deltoid injections, supporting the first twohypotheses. While a measure of the time from injection to thepeak did not appear to differ in either site, this may only be areflection of the limited serum levels that were measured. Adecrease in the elimination rate constant, an increase in thehalf-life and an increase in volume of distribution, combinedwith a non-linear logarithm of serum levels versus time suggestedthat the absorption phase may have been delayed following glutealinjections. Although discomfort was not being measured, it isworth noting that the patient described significant discomfortfollowing deltoid injections.Case #2 Case #2 involved a 28 year old male who sustained anincomplete spinal injury at C4-5 four months prior toparticipating in the study. He presented as a fairly muscularindividual weighing 81 kg. and reaching 6' in height. Althoughthis subject did not meet study inclusion criteria in relation tolevel of injury, an exception was made because sensory and motorreturn post-injury left him with an intact deltoid muscle on theleft side. With motor return limited to his left arm at the timeof the study, he presented with an intact left deltoid muscle, a46partially paralyzed right deltoid muscle, and paralyzed glutealmuscles. A comparison of paralyzed versus non-paralyzed muscleabsorption was done by eliminating the right deltoid muscle as aninjection site. The subject met all other criteria forinclusion. The physician ordered gentamicin 80mg. I.M. B.I.D.for 7 days.Subject #2 was randomly assigned to have the first set ofinjections in the gluteal muscle. Serum samples were drawnbefore and after the fourth injection. Following the collectionof the first set of serum samples, the injection site was changedto the left deltoid. Serum samples were to be taken before andafter the fourth injection in the new site (8th injection intotal). Unfortunately the physician discontinued the gentamicinafter the second deltoid injection and started the patient onCiprofloxacin 500 mg. p.o. B. I. D. for 14 days. This was donein response to receiving the results of sensitivity tests and inresponse to noting much improvement in the client's status.Following discussions with the client and physician, thegentamicin was restarted, but only for three doses. Although thestudy protocol called for four doses, a pre-planned week-end passby the client combined with the physicians's desire to have himon oral antibiotics, and restricted laboratory hours, limited theinjections to three. Twenty-four hours elapsed from the time ofthe last injection before the gentamicin was discontinued untilthe next deltoid injection was given. once the drug wasrestarted serum samples were collected before and after the thirdinjection in the deltoid muscle. Table 3 identifies the serumlevels obtained following injections in each site, and Figure 647Table 3$ublect 2 - Comparative Serum Levels  Serum Levels FollowingSite Specific InjectionsTime Deltoid Muscle^Gluteal Muscle1/2 hr. pre-injection^<0.3ug/m1^0.4ug/m11 hr. post injection 3.0ug/m1 3.6ug/ml2 hr. post injection 2.2ug/ml 2.4ug/ml3 hr. post injection 1.7ug/m1 1.9ug/ml4 hr. post injection 1.3ug/ml 1.3ug/mlvisually displays the findings.According to Yin (1989) replication case studies shouldeither a) predict similiar results (literal replication) or b)produce contrary results but for predictable reasons (theoreticalreplication). This case can be considered a theoreticalreplication because although it has many common features to case#1, it has a unique attribute - the serum levels taken followingdeltoid injections were drawn around the third not the fourthinjection. The literature predicts that steady state is notachieved until the fourth dose, therefore one would anticipatethe serum levels taken before and after the third injection wouldbe lower than serum levels taken at steady state - before andafter the fourth injection (Winter, 1989). While the intent wasto do a literal replication, all of the factors were notFigure 6. Subject #2 - Serum Concentration Time CurveSerum Levels(ug/ml.)43.532.521.510.503 hr. postpointofinjection2 hr. post1 hr. postTime4 hr. post.0. Deltoid SiteGluteal Site1/2 hr preTime Deltoid Glutold1/2 hr. pre <.3 0.41 hr. post 3.0 3.62 hr. post 2.2 2.43 hr. post 1.7 1.94 hr. post 1.3 1.349duplicated. Kennedy notes that Hit is acceptable to defineunique attributes post-hoc" (1979, p. 667). The results of thiscase can be described according to the study hypotheses.The results in Table 3 do not support the first hypothesisrelated to serum trough levels being higher when injections aregiven above the level of injury. The results in this casesuggest that the hypothesis does not hold true when serum levelsfollowing injections in the deltoid are not at steady state andthe serum levels following gluteal injections are at steadystate. From the results one cannot say whether the hypothesiswould have been supported had there been four injections in eachsite.The second hypothesis related to peak serum levels beinggreater when injections are given above the level of injury wasnot supported in case #2. The only difference between this caseand the first one where this hypothesis was supported was thefact that the serum samples were taken around the third injectionin the deltoid site and around the fourth injection in thegluteal site. According to the literature on steady state, onewould expect the peak level to be lower after the third injectionthan after the fourth injection. Once again, the question thatcannot be answered in this case is whether the hypothesis wouldhave been supported if there had been four injections in thedeltoid muscle.The peak levels can be discussed in terms of clinicalsignificance. In this case the peak levels achieved followingfour injections were below the therapeutic range of 4-8ug/ml forboth sites.50In comparing the results of the first case to this one, it isnecessary to separate discussion of the gluteal site findingsfrom the deltoid site findings. The procedure for injections inthe gluteal muscle in case one and two were identical. The serumlevels following four gluteal injections in both cases were foundto be below the therapeutic range. Having two identicalprocedures produce the same results allows one to say that tosome degree replication has taken place. This replicationsuggests that serum levels following gluteal injections of 80mgI.M. may not reach the therapeutic range in persons with a spinalcord injury.The procedure for taking the peak serum levels followingdeltoid injections in case #1 and #2 were not identical. In case#1 the level was taken after four injections and in case #2 thelevel was taken after three injections. In case #1 the level waswithin therapeutic range and in case #2 the peak level was belowthe therapeutic range. Comparing these two cases suggests thattherapeutic levels may be achieved in non-paralyzed muscle onlyafter steady state is reached (four injections).The third hypothesis for this study was that the absorptiontime of I.M. gentamicin is less when injections are given abovethe level of injury than when given below. Figure 6 plots theserum concentration time curve for this subject. While itappears that the absorption time (time to reach the peak level)was one hour for both sites, because of the limited samples, thetrue peak times are not known. The logarithm of serum levelsversus time is depicted in Figure 7. The non-linear appearanceof the plot of the levels for the gluteal site suggests that the1 hr 4 hrs3 hrs2 hrsDeltoid SiteGluteal SiteTime Deltoid Glutold112 hr. pre <.3 0.41 hr. post 3.0 3.62 hr. post 2.2 2.43 hr. post 1.7 1.94 hr. post 1.3 1.3Time Post-injectionFigure 7. Subject #2- Logarithm of Serum Levels vs Time5v) 43OOc/5E 2O52absorption of gentamicin from that site, unlike absorption fromthe deltoid, was not of the first order. In the first case,pharmacokinetic parameters were calculated to assist inpredicting any differences in absorption time related toinjection site. In this case the parameters could not becalculated since the levels for the deltoid site were not atsteady state. The necessary pharmacokinetic calculations cannotbe made if steady state is not achieved (Winter, 1989).While the focus of this study was on serum drug absorption,the issue of discomfort was raised.In response to questions aboutdiscomfort from the injections, the subject in this case did notreport any discomfort in his gluteal site, but reported an achingdiscomfort in his deltoid muscle. He stated "It doesn't hurt, itjust feels like I had a really good work-out yesterday, and I'mfeeling it today".In summary this case differed from the first in that therewere three not four deltoid injections given. The peak andtrough levels were higher following the four gluteal injections,as compared to levels following the three deltoid injections.Neither site had peak levels within the therapeutic range. Whilethe plot of serum levels versus time suggests that there were nodifferences in the absorption times from either site, thelogarithmic plot suggests that absorption was not the same inboth cases. It is worth noting that as in case #1, the subjectin this case commented on discomfort associated with deltoidinjections.53Case 03 The third case involved an 18 year old male whose admittingnotes indicated he had "a T5 burst fracture dislocation withsubsequent complete T5 paraplegia". Two months post-injury hewas noted to have some sensory recovery. For the purposes ofthis study he was still classified as a complete injury becausethere was no recorded motor return.^At three months post injuryhe was ordered gentamicin 80 mg. I.M. q8h for a gram negativebladder infection. His symptoms included a fever of 39 degreesC., sweating, and increased spasms. At the time of the study thesubject weighed 64.5kg and was 5'10". The subject met thecriteria for the study and agreed to participate. In additionparental consent was obtained because of his age. He wasrandomly assigned to receive the first four injections in thedeltoid muscle, followed by four injections in the glutealmuscle. The study protocols were followed. Table 4 and Figure8 display the serum level results.In the same week that the serum samples were collected, thisclient began to recover some motor function in his lowerextremities. While he was involved in the study he had noapparent motor function below the level of injury, but it is notpossible to determine the degree of paralysis of the glutealmuscle at the time of the injections. The subsequent recovery offunction suggested that the gluteal innervation, and blood flowwere probably not reduced to the same extent as in the glutealmuscles of the first two subjects. This case differed from theothers in two ways. The dosage of gentamicin given was higherthan in case 01 and #2, and the gluteal muscle which wasTable 4Eublect 3 - Comparative Serum Levels Serum Levels FollowingSite Specific InjectionsTime^Deltoid Muscle^Gluteal Muscle541/2 hr. pre-injection1 hr. post-injection2 hr. post-injection3 hr. post-injection4 hr. post-injection0.8ug/m14.4ug/ml3.2ug/ml2.3ug/ml1.7ug/m11.6ug/ml4.8ug/ml4.4ug/m13.5ug/ml2.6ug/m1paralyzed in case #1 and #2, was possibly not totally paralyzedin this case. Rather than disregard this case because of thedifferences, it was examined as a theoretical replication inwhich there were known attributes which were unique.The trough levels in this case were both within therapeuticrange (below 2 ug/ml) but they were both notably higher than incase #1 and #2 where the dosage was lower. The hypothesis thatthe trough level would be greater when the injections are givenabove the level of injury did not hold true for this case. Itwas also hypothesized that the peak serum level is greater whenthe injections are given above the level of injury than when theyare given below. In case #2 this second hypothesis was notsupported. The peak serum level following542et)10Timepointofinjection1 hr. post 3 hr. post2 hr. post 4 hr. postDeltoid SiteGluteal Site1/2 hr preTime Deltoid Glutold1/21v. pre OS 161 he. post 44 4.82 hr. post 32  4.43 ht. poet 2.3 3.34 hr. post 1.7 2.63Figure 8. Subject #3 - Serum Concentration Time CurveSerum Levels(ug/ml.)56injections in the gluteal muscle was higher than the peak levelfollowing injections in the deltoid muscle.Of the three cases, this was the only one where both thegluteal and deltoid injections resulted in peak serum levelswithin the therapeutic range. In case #1 therapeutic levels werefound only after injections in the non-paralyzed deltoid muscle.In case #2 therapeutic levels were not achieved with either site.One possible explanation for the higher trough and peak levelsfollowing injections in the gluteal muscle as compared to thedeltoid, in this case, was that the drug may not have beencompletely absorbed between injections. With case #1 and #2injections were given every twelve hours. In this caseinjections were given every eight hours. It is possible the drugwas not completely absorbed within the dosing interval. If thisexplanation was true there would be a compounding effect causingall of the levels in the latter injections (gluteal) to be higherthan in the equivalent levels after the initial injections(deltoid).Another possible, but less likely explanation for much higherserum levels following gluteal rather than deltoid injections isrelated to the return of function experienced by this clientshortly after the levels were drawn. It is a less likelyexplanation because even in comparisons of deltoid and glutealmuscle absorption when both were non-paralyzed (intact neuraxes)Evans (1971) found that the peak levels were lower and the rateof absorption was slower in gluteal versus deltoid muscles.The third hypothesis for this study was that the rate ofabsorption is faster when injections are given above the level of57injury than when given below. While Figure 8 suggests absorptiontime was the same in both sites (peaks at one hour), Figure 9suggests that there were differences in the absorption from eachsite(linear vs nonlinear).Since serum samples were taken around the fourth and eighthinjections, one can assume steady state was achieved, and thusproceed to do the pharmacokinetic calculations. Table 5identifies the elimination phase pharmacokinetic parameterscalculated for this case.Table 5Bublect 3 - Pharmacokinetic Values Parameters^Deltoid Site^Gluteal SiteElimination Rate Constant^0.32h-1^0.29-1Half Life^ 2.2hours^3.4hoursVolume Distribution^14.4 litres^16.8 litresFrom the preceeding table it is apparent that, in this case,there was a smaller elimination rate constant, a larger half lifeand a larger apparent volume of distribution following injectionsin the gluteal muscle than following injections in the deltoidmuscle. Given that this subject had no change in renal functionor fluid status during the study time, these results suggest thatthe absorption phase may have been delayed. The prolongedhalf-life is in keeping with the supposition that higher levelsmay have been found after the gluteal injections because of drugcarry over from one dosing interval to the next.1 hr 4 hrs3 hrs2 hrsFigure 9. Subject #3 - Logarithm of Serum Levels vs Time5v, 430O2tao0FcriDeltoid SiteGluteal Site50.881(Cle.n18Time Deltoid Glutold1/2 hr. pre 0.8 .^1.6I hr. post 4.4 412 hr. post 3.2 4.43 hr. post 23 3.54 hr. post 1.7 2.6Time Post-injection59In addition to the pharmacokinetic data collected for case#3, comments related to comfort were noted. The subjectdescribed discomfort associated with deltoid injections in termsof feeling like he had "been in a fight". He noted that he wassore for a few days.In summary, in this case the dosing interval was shorter thanin the other two cases. Although the subject appeared to haveparalyzed gluteal at the time of injections, he recovered somemotor function within days and this may have affected theabsorption from that site. The trough and peak levels were foundto be higher following gluteal injections. Possibly this wasrelated to drug carryover due to a shorter dosing interval.While the measured peak levels suggested no difference inabsorption times, the elimination phase pharmacokinetics andlogarithm plot suggested otherwise. The decreased eliminationrate constant, increased half-life and increased volume ofdistribution found following gluteal injections as compared todeltoid injections suggested that the absorption time was longerfollowing gluteal injections. This supposition is supported bythe fact that the logarithm of levels related to the deltoidinjections was linear, while the logarithm of levels related togluteal injections was nonlinear. As in the first two cases,this subject described discomfort associated with deltoidinjections.Cases 1-3 The findings reflect support of the hypotheses in some casesbut not in others. However, explanations have been provided forthese differences. The first hypothesis was that serum trough60levels are greater when the injections are given above the levelof the injury than when given below. The second hypothesis wasthat serum peak levels are greater when injections are givenabove the level of injury than when given below. While theresults in case #1 supported both of these hypotheses, contraryresults were found for cases #2 and #3. Possible explanationsfor the contrary results were given.An explanation offered for the contrary results in the secondcase related to achievement of steady state. It is assumed thatsteady state is achieved after the fourth injection, and levelsdrawn before that time will be lower (Winters, 1989). In thesecond case serum samples following deltoid injections were drawnaround the third injection, not the fourth as specified by theprotocol. It is unknown whether the hypotheses would have beensupported if serum samples had been drawn after four injectionsin the deltoid muscle, as they were for the gluteal site in casetwo.One explanation offered for the contrary results in case #3was related to dosing intervals. The dosing interval in case #1and #2 was twelve hours as compared to eight hours in case #3.It was proposed that the results in this case may have reflecteda compounding of the drug due to incomplete elimination betweeninjections. This explanation suggests that higher levels werefound following gluteal injections because the gluteal injectionswere given subsequent to the deltoid injections and reflectcompounded drug accumulation over time. While the subject incase #3 regained some motor function following the study, it isnot likely that this explains the contrary results because one61would expect any differences in a comparison of normal muscles tofavor the hypotheses of this study. Evans (1971) found thatblood flow was slower in "normal" gluteal muscle as compared to"normal" deltoid muscle.The third hypothesis of this study was that absorption timeis longer following injections in gluteal muscle as compared todeltoid muscle. The findings from all three cases tentativelysupported this hypothesis. Doing serum measures one hour apartdid not allow for accurate differentiation between peak times,and thus absorption times. By calculating the pharmacokineticvalues associated with the elimination phase of the drug, and byplotting the logarithm of the serum levels for each site, furtherpredictions could be made about absorption time. In all threecases the elimination rate constant was smaller, the half-lifelonger, and the volume of distribution larger following glutealinjections suggesting a prolonged absorption phase.Rather than refer to statistical significance, when usingcase analysis one may investigate clinical significance. Thetherapeutic peak level for gentamicin administered I.M. isconsidered to be in the range of 4 - 8 ug/ml. In case #1 atherapeutic level was achieved following injections in thedeltoid muscle, but not in the gluteal muscle. In case #2 thefindings in relation to the gluteal muscle were replicated butthe results after only three injections in the deltoid musclewere not within therapeutic range. In case #3 serum levels werewithin the therapeutic range following injections in both sites.Measuring discomfort associated with injections was not aformalized part of this study, but it is worth noting that all62three subjects indicated that deltoid injections resulted insignificant discomfort. Descriptions of discomfort associatedwith deltoid injections ranged from "aching", to "feeling like Ihad been in a fight."SummaryIn this chapter a description of the sample and discussion offactors which may have influenced the sample size were presented.During the period of data collection only seven patients wereordered gentamicin and of those seven, only three were subjectsin this study. Expanding the criteria to include amikacin andtobramycin did not result in any more study subjects. Threepossible influences on sample size were discussed. Theyincluded: a new laboratory protocol, a concurrent research study,and new antibiotics on the market.Because of the small sample size, the methods of dataanalysis originally intended for this study were no longerappropriate. After consultation with a statistician, a decisionwas made to consider the subjects as individual case studies.The results of the three cases were examined in relation to thehypotheses of the study. A summary of the findings was presentedin the form of cross-case analysis. While some findingssupported the hypotheses, others did not. Only in case fil werethe serum trough and peak levels higher following deltoidinjections than following gluteal injections. Possibleexplanations offered for contrary results related to the numberof injections, and the time between injections. The time betweenserum samples was too great to accurately differentiate theabsorption times, but pharmacokinetic values associated with the63elimination phase suggested that absorption was delayed followinginjections below the level of injury. In addition to discussingthe findings in relation to the three hypotheses, the researcherdiscussed the findings in terms of clinical significance, andmade reference to client discomfort associated with deltoidinjections.64CHAPTER FIVESummary, Conclusions, Implications and RecommendationsIntroduction This study was designed to determine the difference in drugabsorption between intramuscular injections given above and belowthe lesion in persons with a spinal cord injury, when the lesionis within the range of C-6 to L-2. This chapter will include anoverview of the study, followed by conclusions, implications forpractice, education and theory, and recommendations for furtherresearch.Summary Staff at a major rehabilitation centre shared with thisresearcher their unsubstantiated belief that I.M. gentamicin didnot seem to be as effective in treating urinary tract infectionsin individuals with spinal cord injury as it was with the generalpopulation. To identify current practice, this researcherconducted a survey of nurses working with patients with a spinalcord injury. The survey revealed that when I.M. injections wereordered nurses generally chose an injection site below the levelof injury to avoid patient discomfort. This researcherquestioned if perhaps there wass a more important factor thancomfort to consider when choosing a site for intramuscularinjections for a person with a spinal cord injury. Wouldabsorption be impaired if injections were given below the levelof injury in paralyzed muscle?The literature suggested that serum drug absorption may beimpaired following intramuscular injections in persons with aspinal cord injury. What was unclear from the literature was65whether absorption was impaired in persons with a spinal cordinjury regardless of the site of injection, or only wheninjections were given below the level of injury in paralyzedmuscle. This study was therefore designed to compare theabsorption of I.M. administered gentamicin above and below thelesion in spinal cord injury.The theoretical framework for this study had its basis inphysiology and pharmacology. The literature identified threecategories of factors affecting serum drug absorption followingintramuscular injection - drug action, area for diffusion, andblood flow. Within each of these categories, the literaturesuggested specific factors influencing absorption. This studycontrolled for all of the factors known to influence serum drugabsorption in order to test the effect of muscle innervation(paralysis) on drug absorption.A review of the literature revealed only three studiesrelated to serum drug absorption following I.M. injections inpersons with spinal cord injury. These studies suggested thatI.M. absorption is impaired when injections are given below thelesion in persons with a spinal cord injury (Segal, 1986 & 1988)and may even be impaired when given above the level of injury(Sankaranarayanan, 1989). One must be cautious in drawingconclusions from the latter study which found impaired absorptionabove the lesion in spinal cord injury because the results mayhave been confounded by the comparison of active individuals tothose who were bedridden. All of the identified studies comparedI.M. absorption in persons with a spinal cord injury to that inable-bodied control subjects. No studies were found which66compared absorption above and below the lesion in spinal cordinjury.The first two hypotheses for this study were that the serumtrough level (1st hypothesis) and peak level (2nd hypothesis) ofgentamicin, following I.M. injections in persons with spinal cordinjury, are greater when the injections are given above the levelof injury than when they are given below. The third hypothesiswas that the absorption time is shorter when injections are givenabove the level of injury as compared to below.This study used an experimental, repeated measures designwith counterbalancing. The subjects acted as their own control byreceiving I.M. injections of gentamicin above and below the levelof injury. Nurse research assistants drew serum samples beforeand after a series of injections in each site to determinedifferences in serum drug absorption.While it was the intention of this researcher to have asample size of 10, the actual sample size was only three after ayear and a half of data collection. The change in sample sizenecessitated a change in the method of data analysis fromone-tailed t-tests for dependent samples to case analysis. Threefactors identified as possibly having influenced sample size werea new laboratory protocol which restricted the urine samplesbeing analyzed; a concurrent research study which limited whenpatients could be treated and with which drugs; and new oralantibiotics on the market which began to replace gentamicin.The sample for this study consisted of three cases. Case #1involved a 29 year old male with a spinal injury at T12 who wasordered gentamicin 80 mg. ql2h. Case #2 involved a 28 year old67male with a spinal injury at C4-5 with the same medication order.Although the patient in case #2 did not meet the criteria interms of level of injury, he was included because post-injuryreturn left him with an intact left deltoid muscle, and aparalyzed gluteal muscle. In case #3 the subject was an 18 yearold male with a spinal injury at T-5. This subject had an orderfor gentamicin 80 mg. Oh. In all three cases serum samples weredrawn following injections above and below the level of injury todetermine differences in absorption.The findings reflected support of the hypotheses by somecases but not for others. In all three cases findings suggestedthat absorption time may be slower following gluteal injectionsas compared to deltoid injections. The findings for each casewere similar in terms of absorption time, but varied in terms ofthe peak and trough levels. Of the three cases, only in case #1were the serum trough and peak levels higher following deltoidinjections than following gluteal injections. The contraryresults may have been related to differences in the number ofinjections and differences in the dosing intervals.The lower peak and trough levels following deltoidinjections, in case #2, may have been because there were onlythree deltoid injections as compared to four gluteal injections.It is possible that the serum levels had not reached steady stateafter only three injections. Of the three cases, this was theonly one where the serum levels following deltoid injections werebelow the therapeutic range. While one would expect higher serumlevels following four deltoid injections, it is not possible topredict what the results would have been had there been four68injections in each site.The lower peak and trough levels following deltoidinjections, in the third case, may have been related to a shorterdosing interval. If absorption was delayed, it is possible thatwith a shorter dosing interval, there was a progressive drugaccumulation over time. The deltoid injections were first,followed by gluteal injections so it is possible that the resultsin this case reflected incomplete elimination within a singledosing interval. This was the only case in which serum levelsfollowing gluteal injections reached a therapeutic level.Because serum samples were drawn one hour apart, differencesin absorption times could not be distinguished by directcalculation. Indirect inferences about absorption were madebased on calculating elimination phase pharmacokinetics. In allthree cases the elimination rate constant was smaller, thehalf-life longer, and the volume of distribution larger followinggluteal injections. Given that the subjects' renal function didnot change during the course of the study, these findings mayhave reflected delayed absorption rather than impairedelimination. Plotting the logarithm of serum levels for eachsite added support to the supposition that absorption may havebeen delayed following gluteal injections.Conclusions With only three subjects, the findings from this researchstudy are by no means conclusive, but a number of inferences orpossible trends have been identified. According to Yin (1989)analytical generalizations can be used whether the case studyinvolves one or several cases because the findings are69generalizable to theoretical propositions, not to populations oruniverses.The trends identified in this study contribute toward therefinement of the theoretical framework related to serum drugabsorption following intramuscular injections. Based on thefindings the following tentative conclusions or trends aresuggested:1. The serum trough and peak levels following injections of 80mg. of gentamicin I.M., in patients with spinal cord injury maybe greater when injections are given above the level of injurythan when they are given below, given the following conditions:serum levels are drawn around the fourth injection (after steadystate is achieved) and the dosing interval is every 12 hours.2. Peak serum levels in the therapeutic range of 4-8 ug/ml arelikely following I.M. injections of gentamicin 80 mg. ql2h innon-paralyzed deltoid muscle, but not likely following similarinjections in paralyzed gluteal muscle.3. Steady state appears to be achieved around the fourth I.M.Injection of gentamicin. Serum levels drawn prior to this timemay be lower than those drawn after steady state is achieved.4. It is possible that injections of 80 mg. of gentamicin I.M. inparalyzed gluteal muscle over a shortened dosing interval (q8h)may result in levels which become progressively higher (evenafter steady state is achieved).5. It is possible that absorption is delayed following injectionsin paralyzed gluteal muscle. Support for this conclusion isbased on two observed trends. Firstly, the elimination rateconstant tends to be lower, the half-life larger, and the70apparent volume of distribution higher following injections inparalyzed gluteal muscle as compared to non-paralyzed deltoidmuscle. This trend seems to hold true regardless of dosinginterval, or number of injections. Given no change in renalfunction, these differences suggest that the absorption phase maybe delayed following injections in paralyzed muscle. Secondly,the logarithmic plotting of serum levels following injections inparalyzed muscle is non-linear, while the same plot followinginjections in non-paralyzed muscle is linear. This supports theproposition that absorption is delayed following injections inparalyzed muscle.Implications for Health Care Professionals The results of this study have implications for a number ofhealth care professionals including nurses, physicians, andpharmacists. Implications are identified in relation topractice, education and theory development. The practice issuesaddressed include site selection, dosing, and drawing serumlevels.Nurses are responsible for selecting the site ofintramuscular injections. In addition to the usual factors to beconsidered such as muscle size, skin condition, amount of drug tobe administered; in patients who have a spinal cord injury,nurses must take into consideration muscle innervation. Nursesneed to be aware that choosing to give injections in paralyzedmuscle may result in slower absorption, and depending on thedosing interval, may result in drug accumulation. Nurses mustchart the site of injections so that serum level results can beaccurately interpreted.71In addition to considering innervation, nurses must takeclient comfort into consideration when selecting injection sites.The subjects in this study described significant discomfortassociated with deltoid injections. The degree of discomfortassociated with injections ranged from slight discomfort, to painwhich interfered with the clients ability to wheel his chair.Discomfort is one of many factors to be weighed by nurses indetermining the best injection site.Physicians order the amount of drug to be administered, theroute of administration, the dosing interval, and any associatedlaboratory work such as serum levels. In ordering gentamicinI.M. a physician generally determines the dosage and dosinginterval based on a patient's ideal body weight and creatinineclearance time. The results of this study suggest that the siteof injections may influence the appropriate dosage and dosinginterval. It is possible that the common protocol of 80 mg. I.M.ql2h will result in underdosing if injections are given inparalyzed muscle. On the other hand, a dosing interval of q8hmay result in drug accumulation since the absorption time appearsto be delayed following injections in paralyzed muscle. If serumlevels suggest that the patient requires more drug, it may bemore appropriate for physicians to increase the dosage ratherthan decrease the dosing interval.It is standard protocol for pre and post injection serumgentamicin levels to be drawn to determine if the dosing isappropriate. There seems to be differing opinions as to when thelevels should be drawn. The results of this study suggest thatit may be best to draw levels around the fourth dose for persons72with a spinal cord injury. It is possible that levels drawnbefore this time may not yet have reached steady state.In addition to having implications for nurses and physicians,the results of this study may be of interest to pharmacists.Frequently, physicians seek dosing advice from pharmacists. Anumber of hospitals have developed empiric dosing guidelines tobe used by physicians. In making recommendations about dosingguidelines for patients with spinal cord injuries, pharmacistsneed to take into consideration the possible effect innervationhas on absorption.The implications of this study extend beyond practice intoeducation. There are implications for inservice and forspecialized education of professionals. In health careagencies/services where persons with spinal cord injuries aretreated, inservice is required. The staff need to be aware ofthe possible delay in absorption with I.M. injections given belowthe level of injury. Nurses must be informed that innervation isone more factor to consider in I.M. site selection. Physiciansand pharmacists need to be aware of the possible implications theresults of this study have when choosing the appropriate I.M.dosing levels and dosing intervals for patients with a spinalcord injury. In addition to the need to educate those currentlyworking with this population, there is a need for educationwithin specialty programs. Students who may work in this fieldin the future need to be aware that innervation may affect I.M.absorption.Besides having implications for practice and education, thisstudy has implications for theory development. The framework for73this study identified a number of factors believed to influenceserum drug absorption. Controlling for these factors allowedthis researcher to test the theory that innervation influencesserum drug absorption. This study has lent some tentativesupport to that theory, and has provided insight into areas forfurther refinement of the framework.Recommendations for, Further Research Further studies need to be done in the area of I.M.absorption and spinal cord injury. The proposition put forthhere that absorption is delayed following injections in paralyzedmuscle needs to be retested. Ideally one would have sufficientsubjects to do an experimental study with statistical analysis.If subjects are limited, further case studies may be conducted.According to Kazdin (1978) the ultimate test of generality offindings among subjects is replication. As well as directreplication of the ideal case, theoretical replications areneeded to determine under what conditions the proposition is notsupported. In theoretical replications one would expect contraryresults for predictable reasons. Attributes which need to bemanipulated include the number of injections prior to levelsbeing drawn, and the dosing interval. Replicate case studiesoffer one option for further research; another option is tocompare absorption above and below the level of injury using atracer substance. With this type of study the sample size wouldnot be dependent on variables beyond the researcher's control.Regardless of the type of study and sample size, there is aneed to draw more serum samples between the time of injection andthe first hour post injection in order to accurately determine74the peak serum levels. Drawing more samples during this timeperiod would provide the researcher with the data necessary tocalculate absorption phase pharmacokinetics such as theabsorption rate constant and the absorption half-life. Drawingconclusions about absorption based on absorption pharmacokineticsis more credible than drawing conclusions about absorptionindirectly from the elimination pharmacokinetics.Further research needs to be done to determine the extent towhich absorption may be delayed following injections in paralyzedmuscle. Delayed absorption results in the drug being present inthe blood stream for longer periods of time. The results of thisstudy suggest that while elimination appears to be complete 12hours post injection, it may not be complete 8 hours postinjection. Progressive serum samples could be drawn following aninjection of gentamicin (or possibly a tracer substance) in orderto determine when no measureable levels of the drug are left inthe blood stream. Knowing this would assist physicians indetermining the most appropriate dosing intervals to achievetherapeutic levels without creating drug accumulation.Steady state is achieved when the rate of drug administrationis equal to the rate of elimination (Winter, 1989, p. 385). Theliterature suggests that steady state may be achieved as early asthe third injection. The findings from this study suggest thatsteady state may not be achieved until around the fourthinjection when gentamicin is given I.M. in paralyzed muscle.This proposition needs to be tested by giving gentamicininjections in paralyzed muscle and measuring the peak and troughserum levels around each progressive injection, starting with the75first injection and continuing until the serum levels stabilize.This will identify the point at which steady state is achieved.Once the time to reach steady state following injections inparalyzed muscle is determined, research is needed to comparethis with the time required to reach steady state followinginjections in non-paralyzed muscle in able-bodied individuals,and following injections in non-paralyzed muscle in persons withspinal cord injury.Nurses frequently choose to give injections in paralyzedmuscle to avoid client discomfort. This study demonstrated thatclient discomfort was a significant factor to consider whenchoosing injection sites for gentamicin. If after consideringall of the factors, a nurse chooses to give an injection belowthe level of injury to avoid discomfort, there may be more thanone site to choose from. Research is needed to determine ifthere are any significant differences in absorption betweendifferent muscle groups - vastus lateralis, gluteal, or deltoid -when all are paralyzed as in higher level spinal cord injuries.In summary, the results of this study suggest that undercertain circumstances absorption is altered in paralyzed muscle.Further research is necessary to validate the findings, and toadd to the existing body of knowledge.^The theoreticalframework for this study offers a basis for future testing andrefinement of hypotheses related to serum drug absorptionfollowing I.M. injections.ReferencesArai, G., Khattar, M., Thuesius, 0., & Pazhoor, A. (1988)Measurements of serum gentamicin concentrations by abiological method, fluorescence polarization immunoassay and enzyme multiplied immunoassay. Clinical Chemistry, 1, 1361-1367.Bauer, F., Cassen, B., Youtcheff, E., & Shoop, D. (1953).Injection half-life with cardiac patients. American Journal of Medical Science, 2A(2), 374-375.Bederka, J., Takemori, A. E., Miller, J. (1971). Absorptionrates of various substances administeredintramuscularly. European Journal of Pharmacology,la, 132-136.Burns, N. & Grove, S. (1987). The practice of nursing research - conduct, critique and utilization. Toronto:W.B. Saunders Company.Canadian Paraplegic Association (1989). National clientstatistics 1988-1989. Author.Cheng, A., Lam, A., & French, G. (1987). Comparativeevaluation of the Abbott TDX, the Abbott ABA200, andthe Syva LAB5000 for assay of serum gentamicin. Journal of Antimicrobial Chemotherapy, 11, 127-133.Dittmar, Sharon. (1989). [Rehabilitation nursing - process and application. St Louis, Missouri:C. V. Mosby Company.Evans, E., Proctor, J., Rotkin, M., Velandia, J.,& Wasserman, A. (1975). Blood flow in muscle groupsand drug absorption. Clinical Pharmacology and Therapeutics, 11.(1), 44-47.Goodman, A., Goodman, L., & Gilman, A. (1980) The pharmacological basis of therapeutics.(6th edition), New York: MacMillan Publishing Co.Greenway, R., Houser, H., Lindan, 0., & Weir, D. (1970).Long-term changes in gross body composition ofparaplegic and quadriplegic patients. paraplegia,2,301-308.Guttman, L. (1974). Spinal Cord Inluries: comprehensive management and research. London:Blackwell Scientific Publications.Gyselynck, A., Forrey, A., & Cutler, R. (1971).Pharmacokineticsof gentamicin: distribution and plasma and renalclearance. Journal of Infectious Diseases, 124,Supplement, 70 - 76.7677Herser, M. & Barlow, T. (1976). Single-case experimental design. New York: Pergamon books.Kazdin, A. E. (1978). Methodological and interpretiveproblems of single-case experimental designs. Journal of Consulting Clinig41 Psychology, j., 629 - 642.Kennedy, M. (1979). Generalizing from single-case studies.Evaluation Quarterly, 2, 661 - 678.Koch-Weser, J. (1974). Bioavailability of drugs (two parts).New England Journal of Medicine, 291, 233-237& 503-506.Martin, N., Holt, N., & Hicks, D. (1981). Comprehensive rehabilitation nursing. New York: McGraw Hill.sankaranarayanan, A., Hemal, A., Pathak, C.,& Vaidyanathan, S. (1989). Serum gentamicin levelsin traumatic paraplegics following intramsucularadministration in non-paralyzed limbs. Journal of Clinical Pharmacology, Therapy & Toxicology, 22(11),540 -543.Segal, J., Brunnemann, S., & Gray, D. (1988). Gentamicinbioavailability and single-dose pharmacokinetics inspinal cord injury. Drug Intelligence and Clinical Pharmacy, 2.2„ 461-465.Segal, J., Brunnemann, S., Gray, D., Gordon, S.,& Eltorai, I. (1986). Impaired absorption ofintramuscularly administered gentamicin inspinal cord injury. Current Therapeutic Research, aim, 961-969.Segal, J., Gray, D., Gordon S., Eltorai, I.,& Khonsari, F. (1984). Pharmacokineticsof gentamicin in patients with spinal cord injury.Clinical Pharmacy, 2, 418-420.Seifert, J., Lob, G., Stoephasius, E. Probst, J., & Brendel,W. (1972). Blood flow in muscles of paraplegic patientsunder various conditions measured by a double isotopetechnique. paraplegia, la, 185-191.Shlafer, M., Marieb, E. (1989). The Nurse, pharmacologyand drug therapy. New York: Addison-WesleyPublishing Co.Sorensen, K., & Luckmann J. (1979). Basic nursing - a psvchophysiological approach.  Toronto: W.Saunders Company.Spurrell, V. (1989). Survey of nurses working with spinalcord injured patients. Unpublished.Swearingen, P. (1991). photo-Atlas of Nursing Procedures.(2nd edition). London: Addison-Wesley Publishing Co.Tandon, S. Pathak, C., Khanduja, K., Malakondia,G., Mahapatra, T., Sankaranarayanan,. A.,Vaidyanathan, S., & Sharma, P. (1987). Alterationin gentamicin pharmacokinetics in acute traumaticparaplegics. Indian Journal of Physiological Pharmacokinetics, 21,(1) 70-72.Tindua, R., Ambrose, P., & Harralson, A. (1983).Aminoglycoside inactivation by penicillins andcephalosporins and its impact on drug-levelmonitoring. Drug Intelligence Clinical Pharmacy,1/, 906-908.Trieschmann, R. (1982). Spinal cord injuries -psychological, social _and vocational adiustplent.Toronto: Pergamon Press.Warwick, R. & Williams, P. (1973). Gray's Anatomy.(35th edition). Great Britain: Jarrold & Sons Ltd.Watson, R., Landon J., Shaw, E., & Smith, D. (1976).Polarization fluoroimmunoassay of gentamicin.Clinica Chimica Acta, 22, 51-55.Winslade, N. (1991). Aminoglycosides and quinolones.On Continuing Practice, 18(3), 5 - 8.Winter, M. (1989). Basic Clinical Pharmacokinetics.(2nd edition). Vancouver, Washington: AppliedTherapeutics.Yin, R. (1989). Case study research - design and methods (rev. ed.). London: Sage Publication.Zellman, s. (1961). Notes on techniques of intramuscularinjection. American Journal of Medical Science,241, 563-574.7879APPENDIX AStudy: Absorption of Intramuscular Injections Above andBelow the Level of a Spinal Cord InjuryInvestigator: Valerie (Leslie) Spurrell R.N., B.S.N.Reasearch Assistants:Anna Krzyzanowoski R.N., Soile SilanderR.N., Colleen Powers R.N., and Lorna Dick R.N.LETTER/CONSENT FORMMy name is Valerie Spurrell. I work in the nursingdepartment at G. F. Strong Centre and am conducting aresearch study to satisfy requirements for my master's thesisat the University of British Columbia.You have a bladder infection which your doctor hasdetermined is best treated with injections of an antibiotic.Research indicates that injections into the buttocks are notabsorbed as well in persons with a spinal cord injury ascompared to able-bodied persons. For this reason a study isbeing done to determine if injections given above the levelof spinal injury (in the arm) are absorbed better than thosegiven below the level of spinal injury (in the buttocks). Itis believed that the results of this study will assist nursesand doctors to make the best choices in terms of effectivelytreating this type of bladder infection.Consenting to be a part of this study means that four ofyour injections will be given above your level of injury (inthe deltoid muscle of the arm) and four will be given belowyour level of injury ( in the gluteal muscle of thebuttocks). At two different points in the course of yourtreatment, five blood samples will be drawn to determine howeffectively the drug is being absorbed into your bloodstream. The samples will be drawn over a 4 1/2 hour period,during which time you will be asked to remain in bed withminimal activity. I also ask permission to see your medicalrecord in order to identify information concerning your levelof spinal cord injury and treatment.Participation in this study is strictly voluntary. Youhave the right not to participate without jeopardy to yourcare. If you agree to participate you have the right towithdraw at any time and your care will in no way beaffected. This study is confidential. Blood samples will becoded so your name is not revealed. If the results show youare receiving too high or too low a dose of the antibiotic,your doctor will be informed. No one else will have accessto the results. You name will not be revealed in anypublications which may result from this study.If you have any questions about the study please feelfree to contact me. My work number is 734-1313 local 323 andmy office is on the fourth floor at G. F. Strong Centre. Mysupervisor is Dr. Ann Hilton. She can be reached at228-7498.80CONSENT FORMI ^  have read and received a copy ofthe preceeding information. I have had the study explainedto me and fully understand what is involved. I agree to be aparticipant in this study.DatePatient's SignatureWitness81APPENDIX BI.M. Infection Procedure 1. Check Dr's order sheet, and check the medication sheet forthe site to be used. This will also be on the medicationvial.2. Check for allergies3. Wash hands.4. Collect equipment: medication, 3 cc syringe, 22G 1 1/2"needle (or appropriate size if the patient7s weight is notwithin normal range.)5. Check medication vial with order. Make dosage calculation.6. Use a filter needle to withdraw medication and thenreplace with the injection needle. If all of the medicationis not used, dispose of remainder in the ampoule7. Rid syringe and needle of air bubbles to measure doseaccurately. Add 0.2 ml of air.8. Identify patient and explain procedure.9. Recheck the appropriate site for injection, and positionpatient accordingly.10. Select the appropriate site for injection using specificanatomical landmarks.To map the deltoid muscle, locate the lower edge of theacromion process with one hand and with the other handidentify the area of the lateral aspect of the upper arm thatis in line with the axilla. The muscle is bounded by animaginary upside-down triangle that can be envisioned betweenthe two hands.To map the dorsal gluteal muscle find the posterior superior82iliac spine. Locate the greater trochanter. The diagonalline that extends from the posterior superior iliac spinetoward the greater trochanter of the femur, and thehorizontal line extending from the posterior superior iliacspine to the lateral hip two fingers' breadth below the iliaccrest, form the boundary for the area that is safe for IMinjections.11. Cleanse the site with alcohol swab using a firm pressurein a circular motion from centre out.12. Spread the tissue between your thumb and index finger tomake the skin taut, and then insert the needle in a quickdart-like motion.13. Supporting the barrel, pull back on the plunger andaspirate for blood. If blood is aspirated, withdraw theneedle and replace the syringe, needle, and medication.14. Inject the medication slowly to minimize discomfort andto evenly distribute the solution.15. Wait 3 seconds before removing the needle and applypressure to the site immediately. Massage the site for oneminute with the swab.16. Record the procedure indicating exact time, site, anddose. (Swearingen, 1984)Posterior superioriliac spineGluteal arteryGluteus mediuscrestSciatic nerveGreater trochanterof the femurDORSAL GLUTEAL INJECTION SITE83—Acromion process—ClavicleDeltoid muscleDeep brachialarteryRadial nerveHumerusDELTOID INJECTION SITE8485APPENDIX CData Collection Sheet Research Assistant:Today's Date:Patient's Code:Diagnosis:Date of injury:Details re: gentamicin eg. dose, date ordered, etc.Current 'other' Medications (including date started):Age:Sex:Description of infection:(type of bacteria)Medical History:Lab values (include any significant tests eg. renal function,cardiac function, hepatic function, aminoglycoside levels,recent urine tests)86First Set of Observations Assistant Name^ DateCode II to be used with blood workPrior to beginning sample collections please ensure staffare informed and therapy is cancelled for the morning so thatthe patient will have limited activity. You may give care tothe patient between samples but please try to limit activityeg. bedrest.1. Site of last three injections2. Time and date of 1/2 hour pre-injection serum sampleComments:(site used,...)3. Time of injection ^Comments: (site, left or right, any variation from procedure,pts comments re pain, number of injections to date....)First Set of Observations 4. Time of 1,2,3 and 4 hour post-injection serum samples.Include comments such as arm used, etc.1 hour post inJection:(sample *2)2 hours:3 hours:4 hours:5. Time delivered to the lab ^6. Other comments8788second Set of Observations Assistants Name^ DateCode ft to be used with blood workPrior to beginning sample collections please ensure staff areinformed and therapy is cancelled for the morning so that thepatient will have limited activity. You may give care to thepatient between samples but please try to limit activity eg.bedrest.1. Site of last three injections ^2. Time and date of 1/2 hour pre-injection serum sampleComments:(site used,...)3. Time of injection ^Comments: (site, left or right, any variation from procedure,pts comments re pain, number of injections to date....)4. Time of 1,2,3 and 4 hour post-injection serum samples.Include comments such as arm used, etc.1 hour post inJection:(sample #2)2 hours:3 hours:4 hours:5. Time delivered to the lab ^6. Other comments8990APPENDIX DVenipuncture Procedure 1. Wash hands and collect venipucture cart.2. Identify patient and explain procedure.3. Aseptically screw the double-ended needle into the plasticouter vacutainer, with the shorter needle positioned insidethe outer container. Then insert a tiger-top vacuum tubeinto the outer container with the rubber stopper of the tuberesting against the shorter needle.4. Choose either the median basilic or cephalic vein.Observe and palpate for an appropriate site within theantecubital space.5. Place the patient's arm in a supported position.6. Wrap the tourniquet a few inches above the site. Itshould be tight enough to impede venous flow but not so tightthat it occludes the arteries. You should still be able topalpate an arterial pulse distal to the tourniquet.7. Cleanse the area with an alcohol swab using a circularmotion and working outwards. Let the solution dry.8. Stabilize and anchor the vein distal to the insertionsite. With the needle's bevel up, insert it into the vein ata 30 to 45 degree angle. After puncturing the vein,stabilize the plastic outer container, and gently yet firmlyadvance the vacuum tube to pierce the rubber stoppper withthe short needle. Because of the vacuum, bllod shouldimmediately begin spurting into the vacuum tube. As soon asit does, release the tourniquet. Collect a minimum of 2ccand then remove the vacuum tube.919. Remove the needle from the vein and apply pressure with asterile sponge for 1-3 minutes to stop the bleeding. oncethe bleeding has ceased, place a bandage over the puncturesite.10. Label the tube including date time, which sample eg. (1/2hr pre, 1 hr post...), site of injection, drug and dose.Place specimen in the fridge until all five have beencollected and then deliver to accessioning at Shaughnessy Lab(Searingen, 1984).92APPENDIX EEquations for Calculating Pharmacokinetic Parameters Elimination Rate Constant (Kd) The elimination rate constant is the fraction or percentageof the total amount of drug in the body removed per unit of time(Winter, 1989, p.40).Kd = QaCt tCp = the highest (peak) plasma level measured (ug/ml)Ct = the lowest post-injection level measured (ug/mi)t = the time interval between Cp and CtRalf-life (t1/2) The half-life is the inverse of Kd and is defined as "theamount of time required for the total amount of drug in the bodyor the plasma concentration to decrease by half" (Winter, 1989,p. 43).t1/2 = 0.693 or ^(natural log of 2) Kd^(elimination rate constant)Volume of Distribution (Vd) "The volume of distribution for a drug or 'apparent volume ofdistribution' does not necessarily refer to any identifiablecompartment in the body. It is simply the size of thecompartment necessary to account for the total amount of drug inthe body if it were present throughout the body at the sameconcentration found in the plasma" (Winter, 1989, p. 21).Vd = ^ Dose (mg) _Cu_ -^(Ct)(e-KdT)e-Kdt93Cp = peak serum level (ug/mi)Ct = post-injection trough level (ug/ml)Kd = elimination rate constantt = extrapolated back calculation of time from peak to time zeroT = extrapolated forward calculation of time from trough leveluntil time zero94APPENDIX FConcurrent Research Study - Definitions Bacteriuria: Isolation of 2105 cfu/ml of midcatheter urine; or102-105 cfu/ml from 2 consecutive specimens; or 102-105 cfu/mlfrom 1 specimen when frankly symptomatic.Symptomatic bacteriuria: BU plus (1) fever , 38oC and suprapubicor flank pain or tenderness; or (ii) epididymo-orchitis,periurethral abscess or prostatic abscess; or (iii) bacteremia.Sacteriuria with fever: BU with fever Z38oC and no otherclinically evident source of fever.Asymptomatic bacteriuria: BU not fulfilling criteria b) and c)above.

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